Oral Tablet Suitable For Active Pharmaceutical Ingredients

ABSTRACT

The invention relates to an oral delivery tablet suitable for active pharmaceutical ingredients comprising a population of particles, the population of particles comprising a) directly compressible (DC) sugar alcohol particles, b) non-directly compressible (non-DC) sugar alcohol particles and c) particles comprising gum base, the non-DC particles providing the tablet with a plurality of discrete non-DC areas, and the non-DC areas resulting in induced saliva generation upon mastication of the tablet, wherein the tablet is designed to be masticated into a coherent residual containing water-insoluble components.

FIELD OF THE INVENTION

The invention relates to an oral tablet suitable for active ingredients,such as active pharmaceutical ingredients.

BACKGROUND OF THE INVENTION

In the prior art it is well-known with chewable tablets and lozengeswhere a substantial part of the delivery vehicle is comprised of a sugaralcohol. It is also well-known that such delivery vehicles may beapplied for delivery of active ingredients.

A challenge related to such delivery vehicles is that the user is moreand more focused on convenience and extended functionality. Suchrequirements do very often conflict with what is technically possible.

EP application 0 922 464 A1 discloses a quickly disintegrablecompression-molded material such as tablets produced throughconventional tableting processes. The tablets comprise granulatederythritol and exhibits rapid disintegration and dissolution when placedin the oral cavity or water.

EP 0 922 464 is thus a representative example of one of many referencesusing granulated polyols, such as erythritol for compressed tablets.

It is an object of the invention to obtain an oral tablet which is ableto promote salivation generation.

SUMMARY OF THE INVENTION

The invention relates to an oral delivery tablet suitable for activepharmaceutical ingredients comprising a population of particles, thepopulation of particles comprising a) directly compressible (DC) sugaralcohol particles, b) non-directly compressible (non-DC) sugar alcoholparticles and c) particles comprising gum base, the non-DC particlesproviding the tablet with a plurality of discrete non-DC areas, and thenon-DC areas resulting in induced saliva generation upon mastication ofthe tablet, wherein the tablet is designed to be masticated into acoherent residual containing water-insoluble components.

Besides several other advantageous the inventive oral tablet exhibits animpressing initial chew feel due to the fact that saliva generation isat least partly promoted by the applied non-DC sugar alcohol.

It is thus noted that the initial cohering of the particles comprisinggum base are improved through the use of the non-DC sugar alcohol, butalso that several other advantages with respect to texture, taste andmouthfeel may be easily obtained within the scope of the invention. Sucheffects include taste masking, flavor burst, improvement of sweetness,etc.

Other advantageous applications within the scope of the inventioninclude the use of the oral tablet for active ingredients, such asactive pharmaceutical ingredients, and oral care, such as dental care.The oral tablet is thus a very attractive carrier of typical ingredientsrelevant for oral care, such as anti-plaque agent, whiteners,anti-bacterial agents, etc. It is here noted that the improvedsalivation effect of the tablet is the perfect match in relation to anoral tablet which may as such be used as a carrier of relevant activeingredients, but the coherent residue may from the start of masticationand may subsequently serve as an abrasive even after most of the oralcare ingredients has been released.

Another advantageous application within the scope of the invention isrelated to nutraceuticals. Several nutraceuticals may easily be carriedand released from the inventive oral tablet, but the increasedsalivation effect may also serve as advantageous promoter of releasefrom both the tablet matrix but also from nutraceutical mixed with thecoherent residue during the initial chewing.

The inventive oral delivery tablet utilizes non-DC sugar alcohols as ameans for both increasing saliva generation and thereby promote the userexperience of the delivery tablet as such but also for an attractiveinitial mastication of the particles containing gum base. The non-DCsugar alcohols thus interact with the particles comprising gum base inthe sense that saliva is present during mastication in an increasedamount; and at the same time, the non-DC sugar alcohol provides anattractive sweetness and taste during and after the mastication process.

The specific use of a relatively high proportion of elastomer in the gumbase may effectively be used for modification of the release of activeingredients in terms of time and amount and the elastomer may alsoprovide robust structure of the tablet facilitating that it is chewedinto a coherent residual containing water-insoluble components. Someactive ingredient may risk invoking disintegration of the residualwhereas an elastomer may increase the coherence and compensate for theaggressive active ingredients.

In the present context, the non-DC sugar alcohol particles areunderstood and defined by the skilled person with reference to theirtypical commercial trade grade.

In an embodiment of the invention, the non-DC sugar alcohol particleshave not been granulated prior to tableting.

Thus, the non-DC sugar alcohol particles are provided as non-granulatedparticles.

These are typically available in a non-DC form of the relevant sugaralcohol as particles which have not been preprocessed by granulationwith other sugar alcohols or binders for the purpose of obtainingso-called direct compressible particles (DC) on the basis of sugaralcohol particles which are by themselves not suitable for directcompression. Such non-DC particles of sugar alcohol may typicallyconsist of the sugar alcohol or at least comprise very high quantitiesof the sugar alcohol. Therefore, non-DC sugar alcohol particles may beparticles consisting of sugar alcohol, which is non-directlycompressible in its pure form. Examples of sugar alcohols which arenon-directly compressible when provided as particles consisting of thesugar alcohol in question include erythritol, xylitol, maltitol,mannitol, lactitol, isomalt, etc.

As a supplementing explanation, many of the most relevant sugar alcoholsin relation to the present invention is those sugar alcohols which areavailable in specially adapted DC-grades obtained through granulationwith another compound, typically a binder.

Therefore, preferred non-DC grades of sugar alcohol may include puresugar alcohol particles.

In an embodiment of the invention, the non-DC sugar alcohol particlesare selected from non-DC particles of erythritol, maltitol, xylitol,isomalt, lactitol, mannitol, and combinations thereof.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained.

According to an embodiment of the invention, the non-DC sugar alcoholparticles consist of sugar alcohols selected from erythritol, maltitol,xylitol, isomalt, lactitol, mannitol, and combinations thereof.

In an embodiment of the invention, the non-DC sugar alcohol particlesare selected from non-DC particles of erythritol, maltitol, xylitol,isomalt, and combinations thereof.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained.

In an embodiment of the invention, the non-DC sugar alcohol particlesare selected from non-DC particles of erythritol, maltitol, xylitol, andcombinations thereof.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained. Also, when a cooling sensation isdesirable, having non-DC sugar alcohol particles comprising orconsisting of erythritol, xylitol, or combinations thereof advantageous.

In an embodiment of the invention, the non-DC sugar alcohol particlesare non-DC erythritol particles.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained, together with a cooling sensation.

In an embodiment of the invention, the non-DC sugar alcohol particlesare non-DC xylitol particles.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained, together with a cooling sensation.

In an embodiment of the invention, the tablet comprises said non-DCsugar alcohol particles in an amount of at least 10% by weight of thetablet.

In an embodiment, the oral tablet comprises one or more activeingredients.

In an embodiment, the oral tablet comprises one or more activeingredients in an amount of 0.5 to 60% by weight of the oral tablet,such as 0.5. to 50% by weight of the tablet, such as 0.5 to 40% byweight of the oral tablet.

In an embodiment of the invention, the active ingredient is anutraceutical.

In an embodiment of the invention, the active ingredient comprises oneor more oral care ingredients.

In the present context, the term “nutraceutical” refers to apharmaceutical-grade and standardized nutrient.

In an embodiment of the invention, the tablet comprises flavor in anamount of 1-10% by weight of the tablet.

According to an embodiment of the invention, the tablet comprises flavorin an amount of 1-6% by weight of the tablet, such as 2-6% by weight ofthe tablet.

In embodiments of the present invention, the tablet comprises one ormore flavoring agents selected from the group consisting of essentialoils, essences, extracts, powders, acids, coconut, coffee, chocolate,vanilla, grape fruit, orange, lime, menthol, liquorice, caramel aroma,honey aroma, peanut, walnut, cashew, hazelnut, almonds, pineapple,strawberry, raspberry, apple, pear, peach, apricot, blackberry, cherry,pineapple, plum essence, clove oil, bay oil, anise, thyme, cedar leafoil, nutmeg, cinnamon, peppermint, wintergreen, spearmint, eucalyptus,mint, or any combination thereof.

In an embodiment of the invention the flavor is a powder flavor.

In an embodiment of the invention the tablet comprises a first modulecomprising at least a part of the population of particles, the firstmodule comprising at least a portion of the flavor.

In an embodiment of the invention the tablet comprises a second modulecomprising at least a part of the population of particles or a secondpopulation of particles, the second module comprising at least a portionof the flavor.

In an embodiment of the invention, the tablet is designed to release atleast 50% by weight of the flavor within 20 seconds from onset ofmastication.

The above release of flavor applies at a chew rate of one chew persecond.

In an embodiment of the invention, the gum base comprises at least 5% byweight of elastomer.

In an embodiment of the invention, the gum base comprises at least 10%by weight of elastomer.

In an embodiment of the invention, the elastomer is selected fromstyrene-butadiene rubber (SBR), butyl rubber, polyisobutylene (FIB), andcombinations thereof and the gum base comprises at least 15% by weightof elastomer.

In an embodiment of the invention, the elastomer is selected fromstyrene-butadiene rubber (SBR), butyl rubber, polyisobutylene (FIB), andcombinations thereof and the gum base comprises between 15% and 25% byweight of elastomer.

In an embodiment of the invention the gum base comprises at least 15% byweight of elastomer.

In an embodiment of the invention the gum base comprises between 15% and25% by weight of elastomer.

In an embodiment of the invention the gum base comprises between 17% and23% by weight of elastomer.

In an embodiment of the invention, the tablet comprises at least 1% byweight of elastomer.

In an embodiment of the invention, the elastomer is selected fromstyrene-butadiene rubber (SBR), butyl rubber, polyisobutylene (FIB), andcombinations thereof.

The applied elastomer may within the scope of the invention also includepolyvinyl acetate (PVA). It is well-known within the art that PVA may beapplied both as an elastomer or as a resin. The application of PVAtypically depends on the molecular weight of the PVA. Within the presentinvention, PVA may be applied as an elastomer when having an averagemolecular weight (Mw) of 50000 g/mol or higher.

Conversely, within the present invention, PVA may be applied as a resinwhen having an average molecular weight (Mw) below 50000 g/mol.

In an embodiment of the invention, the tablet comprises a first moduleand a second module. The first module may e.g. comprise a) DC sugaralcohol particles and b) non-DC sugar alcohol particles. The secondmodule may comprise c) particles comprising gum base.

In an advantageous embodiment of the invention said population ofparticles is tableted into a first module and combined with a secondpopulation of particles that is tableted into a second module.

In an advantageous embodiment of the invention a) and b) is comprised ina first module and c) is comprised in a second module.

Thus, the tablet comprises a first module and a second module, the firstmodule comprising a) DC sugar alcohol particles and b) non-DC sugaralcohol particles, the second module comprising c) particles comprisinggum base.

In an advantageous embodiment of the invention a) and b) is tabletedinto a first module and c) is tableted into a second module, wherein thefirst module is free of gum base.

Thus, a) DC sugar alcohol particles and b) non-DC sugar alcoholparticles are tableted into a first, gum base free module whereas and c)particles comprising gum base are tableted into a second module. Thesecond module may or may not comprise DC sugar alcohol particles and/ornon-DC sugar alcohol particles.

In an advantageous embodiment of the invention a) and b) is tabletedinto a first module and c) is tableted into a second module.

In an embodiment of the invention, the particles comprising gum basehave an average particle size of at least 400 μm, such as between 400 μmand 1400 μm.

According to an embodiment of the invention, the particles comprisinggum base consists of gum base. When the particles comprising gum baseconsists of gum base, they typically have an average particle sizebetween 800 μm and 1400 μm.

In an embodiment of the invention, the tablet comprises at least 20% byweight of gum base.

In an embodiment of the invention the tablet comprises at least 30% byweight of gum base.

In an embodiment of the invention the tablet comprises between 20% and60% by weight of gum base.

In an embodiment of the invention, the gum base comprises at least 5% byweight of resins.

According to an advantageous embodiment of the invention, the gum basecomprises at least 10% by weight of resins, such as at least 15% byweight of resins, such as at least 20% by weight of resins.

According to a further advantageous embodiment of the invention, the gumbase comprises at least 30% by weight of resins, such as at least 40% byweight of resins, such as at least 45% by weight of resins.

In an advantageous embodiment the content of resin is from 40-60% byweight of the gum base.

In an embodiment of the invention, the, the gum resins are selected fromthe natural resins and/or synthetic resins including low molecularweight polyvinyl acetate (PVA).

In an embodiment of the invention, the particles comprising gum basecomprises gum base in an amount of 20-99.9% by weight.

In an embodiment of the invention, the particles comprising gum baseconsists of gum base.

In an embodiment of the invention, the tablet comprises

-   -   elastomer in the range of 1-15% by weight of the tablet,    -   natural and/or synthetic resin in the range of 5-35% by weight        of the tablet,    -   water insoluble components different from the elastomer and        resin in the range of 5-30% by weight of the tablet, and    -   water soluble components, such as sugar alcohols, in the range        of 50-89% by weight of the tablet.

Water insoluble components different from the elastomer and resin in therange of 5-30% by weight of the tablet e.g. includes softeners andfillers.

In an embodiment of the invention the tablet comprises water solublecomponents, such as sugar alcohols, in the range of 30-89% by weight ofthe tablet.

In an embodiment of the invention, a) and b) is comprised in a firstmodule and c) is comprised in a second module, wherein c) the particlescomprising gum base comprises—elastomer in the range of 1-15% by weightof the tablet,

-   -   natural and/or synthetic resin in the range of 5-35% by weight        of the tablet,    -   water insoluble components different from the elastomer and        resin in the range of 5-30% by weight of the tablet, and    -   water soluble components, such as sugar alcohols, in the range        of 20-89% by weight of the tablet.

Water insoluble components different from the elastomer and resin in therange of 5-30% by weight of the tablet gum e.g. includes softeners andfillers.

In a further embodiment, a) and b) is comprised in a first module and c)is comprised in a second module, wherein c) the particles comprising gumbase comprises, wherein the second module comprise water solublecomponents, such as sugar alcohols, in the range of 50-89% by weight ofthe tablet.

Thus, a synergy between utilization of non-DC sugar alcohol particles asa disintegration promoter due to the lower mechanical strength and alsoas a salivation promoter in combination with a second module, which canprovide additional mechanical strength, thereby acting as a carriermodule. This is especially advantageous when the second modulecontributes to an attractive mouthfeel by a high content of DC sugaralcohols and particles comprising gum base, which also providesmechanical strength to the tablet. The advantageous disintegration thusof course refers to a module containing no gum base, but it may alsorefer to a module having a population of particles comprising gum base,as these gum base-containing particles may initially be kept in a sugaralcohol matrix which needs to be disintegrated and dissolved very fastduring the initial mastication.

One advantage of the above embodiment may be that the second module mayhave a higher mechanical strength, e.g. by means of a differentcomposition comprising e.g. a very large amount of direct compressibleingredients, such as DC sugar alcohols and particles comprising gumbase.

A further advantage of the above embodiment may be that the secondmodule may have a higher loading capacity for e.g. active ingredients,partly due to the higher obtainable mechanical strength achievable bylarge amounts of direct compressible ingredients, such as DC sugaralcohols and particles comprising gum base.

Thus, in an embodiment a) and b) is comprised in a first module and c)is comprised in a second module, and c) the particles comprising gumbase comprises. The first module may be tableted before the secondmodule, or vice versa. The particles comprising gum base are included inthe second module. Alternatively, the particles comprising gum base maybe included in the first module or in both the first and second modules.In some embodiments, the tablet may comprise one or more furthermodules. When the gum base is present in one module, the gum basecontaining module is preferable tableted first. The further module mayalso comprise particles comprising gum base, or be free of gum base.

In an embodiment of the invention the oral tablet comprises at least twomodules. A module in the context of the invention is referring to agroup of particles which has been compressed into a volume which iscomparable to the size of the tablet in the sense that it is notinsignificant compared to the tablet. A tablet comprising two or moremodules will thus have module sizes which each are comparable to thevolume of the complete tablet. Comparable in the present context meansthat the modules are not understood as small particles and a moduleshould at least be greater than 1/20 of the complete tablet volume,preferably greater than 1/10 of the complete tablet volume.

The module may typically be gathered from a plurality of compressedparticles and have a weight which is greater than 0.2 gram and less than10.

In an embodiment of the invention a module is defined as a plurality ofparticles being compressed together to form a gathered module ofparticles.

In an embodiment of the invention the oral tablet comprises a pluralityof oral tablet modules. In the present context the application of e.g.two modules are in particular advantageous as the use of non-DC sugaralcohols by nature may result in a more fragile tablet or at least themodule in which the non-DC sugar alcohols are. In other words, non-DCsugar alcohols may be present primarily in one module thereby optimizingthe desired salivation and sensory experience from the module and thetablet as such whereas another module may serve as a support ensuringthat the desired stability and friability of the complete tablet isobtained.

According to an embodiment of the invention, the tablet has two modules.Optionally, a coating may be applied around the two modules to form thefinal tablet.

An advantage of using two modules is described above, but it should alsobe noted that this effect may also be obtained when applying layers ofvery different nature. Such application may e.g. include the use of agum module and a non-gum module, where the non-gum module is containingthe non-DC sugar alcohol particles. In this way, the non-gum layer mayrelease the advantageous non-DC sugar alcohols and the gum layer mayboth stabilize the tablet as described above but also interact with thenon-DC sugar alcohols during in particular the initial release forestablishment of a very pleasant and impressing initial chew phase. Thisincludes and increased saliva and moisture experience.

In an embodiment of the invention the tablet comprises a first modulehaving a first composition and a second module having a secondcomposition, where the first composition is different from the secondcomposition.

In an embodiment of the invention a) and b) is comprised in a firstmodule and c) is comprised in a second module, where the second moduleis free of non-DC sugar alcohols.

In one embodiment, the second module comprises a large amount of DCsugar alcohols, such as larger amounts than the first module. Forexample, the second module may comprise at least 30% by weight of DCsugar alcohols, such as at least 50% by weight of DC sugar alcohols,such as at least 70% by weight of sugar alcohols. In an exampleembodiment, the module may comprise between 50 and 99.9% by weight ofsugar alcohols, such as between 70 and 99% by weight of sugar alcohols.

The amount of DC sugar alcohol may depend on the type and amount ofactive ingredient applied in the tablet, as well as the amount of gumbase used in the tablet.

In an embodiment of the invention the second module is tableted beforethe first module.

In an embodiment of the invention, the non-DC particles providing thetablet with a plurality of discrete non-DC areas, where the non-DC areasare evenly distributed in the tablet or at least one module of thetablet.

One advantage of the above embodiment may be that the even distributionof the non-DC areas promotes an effective disintegration of the moduleupon mastication, e.g. due to lower mechanical strength contributionfrom the non-DC particles, thereby facilitating effective contacting ofthe resulting mastication fragments formed by the mastication withsaliva, again increasing dissolving of a part of the tablet. Also, theeven distribution of the non-DC areas promotes a high number ofmastication fragments with non-DC sugar alcohols, which againeffectively promotes salivation. Thus, a synergy between utilization ofnon-DC sugar alcohol particles as a disintegration promoter due to thelower mechanical strength and also as a salivation promoter incombination with the even distribution to facilitate effect dispersionof mastication fragments in the oral cavity upon mastication.

In an embodiment of the invention, the non-DC particles provide thetablet with a plurality of discrete non-DC areas, where the non-DC areasare evenly distributed in a gum base free module of the tablet.

In an embodiment of the invention, the non-DC particles provides thetablet with a plurality of discrete non-DC areas.

In an embodiment of the invention, a series of at least 10 of saidtablets each comprising a gum base free module, the gum base free modulecomprising said non-DC sugar alcohol particles in an amount varying witha relative standard deviation (RSD) below 10%.

One advantage of the above embodiment may be that uniform product may beobtained having low variation in the amount of non-DC sugar alcoholbetween gum base free modules of tablets. Consequently, thefunctionality provided by non-DC areas in the gum base free modules ofthe tablet may provide low variation between tablets.

It is noted that the reference to RSD and a sequence of tabletstypically refers to a tablet series of a production line.

Furthermore, the RSD of the non-DC sugar alcohol between gum base freemodules of the tablets is a measure of the degree of even distributionof the non-DC areas. Therefore, having an RSD below 10% in a series ofat least 10 tablets indicates an even distribution of the non-DC areasprovided by the non-DC sugar alcohol particles. Having evenlydistributed non-DC areas facilitates a high salivation since the non-DCareas are effectively distributed in the mouth upon mastication and aresulting disintegration of at least a module or part of the tablet.

In an embodiment of the invention, a series of at least 10 of saidtablets comprises a gum base free module comprising said non-DC sugaralcohol particles in an amount varying with a relative standarddeviation (RSD) below 5%.

An advantageous method of dosing non-DC sugar alcohols into acomposition for a large number of tablets has been established, whichfacilitates an exact dosing of the non-DC sugar alcohols in a series oftablets. This means that large-scale production of tablets comprisingnon-DC sugar alcohols is made possible with improved results concerningdistribution of the non-DC areas in the tablets and thereby an improvedRSD between the gum base free modules of the tablets of a series.

The term RSD as used herein is short for the relative standarddeviation, which within this present field is used to indicate theuniformity in content of non-DC sugar alcohols in a series of gum basefree modules of the tablets. An analysis may be carried out on an arrayof 10 tablets of a series, wherein the content of the non-DC sugaralcohols in question is measured. From these values the RSD may becalculated through the standard formula of

RSD=(standard deviation of array X)*100%/(average of array X).

In some cases, it may be most convenient to measure RSD of the amount ofnon-DC sugar alcohol particles indirectly. For example, the RSD ofanother ingredient may be used as an indicator for the amount of non-DCsugar alcohol particles, as segregation affects the whole composition ofthe tablet or module in question.

When attempting to obtain a high degree of even distribution of thenon-DC areas, insufficient mixing may lead to uneven distribution, suchas undesirable agglomeration of particles within certain parts of thetablet. Also, even if mixing very thoroughly the ingredients, anundesirable handling of the mixture from the mixing to a tabletingmachine may lead to segregation. For example, smaller particles maytypically segregate to the bottom part of a container, thereby leadingto different particle distributions for different tablets. Particularlywhen the different ingredients have different particle sizes, e.g. ifnon-DC particles have a larger particle size compared to otheringredients, segregation may lead to different contents of non-DC sugaralcohols in different tablets. Yet, another aspect is that even storinga thoroughly mixed composition for too long may lead to segregation.

On the other hand, a measure of having obtained even distribution ofnon-DC areas in at least one module of the tablet may be that a seriesof at least 10 of the tablets holds a relative standard deviation (RSD)below 10% with respect to the non-DC sugar alcohol content.

In is noted that the term segregation as used herein would be known tothe skilled person to mean the separation of a mixture according tosimilarity, typically size. This may in the present context be a problemwhen handling a mixture comprising very different sizes of particles,e.g. in a hopper for holding and feeding the composition via a feedingmechanism to a die cavity.

Particularly, when including an active ingredient in the tablet, havinga low RSD on the content of such active ingredients is highly desirable.

In an embodiment of the invention, the non-DC particles are providingthe tablet with a plurality of discrete non-DC areas, where the non-DCareas are homogenously distributed in the tablet or at least one moduleof the tablet.

One advantage of the above embodiment may be that the homogenousdistribution of the non-DC areas promotes an effective disintegration ofthe module upon mastication, e.g. due to lower mechanical strengthcontribution from the non-DC particles, thereby facilitating effectivecontacting of the resulting mastication fragments formed by themastication with saliva, again increasing dissolving of a part of thetablet. Also, the homogenous distribution of the non-DC areas promotes ahigh number of mastication fragments with non-DC sugar alcohols, whichagain effectively promotes salivation. Thus, a synergy betweenutilization of non-DC sugar alcohol particles as a disintegrationpromoter due to the lower mechanical strength and also as a salivationpromoter in combination with the homogenous distribution to facilitateeffect dispersion of mastication fragments in the oral cavity uponmastication.

In an embodiment of the invention, the non-DC particles provide thetablet with a plurality of discrete non-DC areas, where the non-DC areasare homogenously distributed in a gum base free module of the tablet.

In an embodiment of the invention, at least 10% by weight of saidpopulation of particles have a particles size below 250 μm, and whereinat least 30% by weight of said population of particles have a particlessize above 500 μm.

According to an embodiment of the invention, the population of particleshave a particle size distribution with a full width at half maximum(FWHM) of at least 100 μm.

Particularly when having a broad particle size distribution of thepopulation of particles, it was surprising to the inventor that evendistribution of the non-DC areas could be accomplished. Typically, whenhaving a broad particle size distribution, such as when having a widthfrom the 10% quantile to the 90% quantile greater than 30% of the meanvalue, associated compositions are considered vulnerable to segregation.However, according to an embodiment of the invention, the non-DC areasare evenly distributed in at least one module of the tablet and may haveamounts of non-DC particles between a series of at least 10 of thetablets holding a relative standard deviation (RSD) below 10%.

According to an embodiment of the invention, the non-DC sugar alcoholparticles have an average non-DC sugar alcohol particle size at least 50μm larger than an average DC particle size of the DC sugar alcoholparticles.

In an embodiment of the invention, the DC sugar alcohol particlescomprises sugar alcohols selected from DC particles of sorbitol,erythritol, xylitol, lactitol, maltitol, mannitol, isomalt, andcombinations thereof.

Sorbitol is an example of a sugar alcohol, which is considered DC grade,when provided as particles consisting of sorbitol, i.e. in its pureform. On the other hand, several other sugar alcohols are considerednon-DC grade if providing them as particles consisting of the specificsugar alcohol. Therefore, such non-DC sugar alcohols are conventionallyprocessed into DC grade sugar alcohols, e.g. by granulating them withe.g. a binder.

Examples of trade grades of DC sugar alcohols include sorbitol particlesprovided as e.g. Neosorb P 300 DC from Roquette, mannitol particlesprovided as e.g. Pearlitol® 300DC or Pearlitol 200 SD from Roquette,maltitol provided as e.g. SweetPearl® P 300 DC, xylitol provided as e.g.Xylisorb® 200 DC or Xylitab 200 from Dupont.

In an embodiment of the invention, the tablet comprises said DC sugaralcohol particles in an amount of at least 10% by weight of the tablet.

According to an embodiment of the invention, said population ofparticles comprises DC sugar alcohol particles in an amount of at least10% by weight.

According to an embodiment of the invention, the first module comprisesDC sugar alcohol particles in an amount of at least 10% by weight.

In an embodiment of the invention, the second module comprises DC sugaralcohol particles in an amount of at least 30% by weight of the secondmodule.

In an embodiment of the invention, the second module comprises DC sugaralcohol particles in an amount of at least 50% by weight of the secondmodule.

In an embodiment of the invention the DC sugar alcohol particles in thesecond module are selected from DC particles of sorbitol, erythritol,xylitol, lactitol, maltitol, mannitol, isomalt, and combinationsthereof.

In an embodiment of the invention, friability of the tablet is less than3%, such as less than 2.5%, such as less than 2%, such as less than1.5%, such as less than 1%, wherein friability is measured according toEuropean Pharmacopoeia 9.1, test method 2.9.7. by using a pharmaceuticalfriability-tester PTF 10E from Pharma Test.

One advantage of the above embodiment may be that a tablet with arelatively high mechanical stability is obtained, while at the same timehaving the desirable mouthfeel of the invention.

According to an embodiment of the invention, friability of the tablet isbetween 0.2% and 3%, such as between 0.5% and 2% wherein friability ismeasured according to European Pharmacopoeia 9.1, test method 2.9.7. byusing a pharmaceutical friability-tester PTF 10E from Pharma Test.

In an embodiment of the invention, the tablet comprises one or morebinders other than binders forming part of the DC sugar alcoholparticles in an amount of 0.1 to 6% by weight of the tablet.

Suitable binders include Gum Arabic, Methyl Cellulose, Liquid glucose,Tragacanth, Ethyl Cellulose, Gelatin, Hydroxy Propyl Methyl Cellulose(HPMC), Starches, Hydroxy Propyl Cellulose (HPC), Pregelatinized Starch,Sodium Carboxy Methyl Cellulose (NaCMC), Alginic Acid, PolyvinylPyrrolidone (PVP), Maltodextrine (MD); Cellulose, Polyethylene Glycol(PEG), Polyvinyl Alcohols, Polymethacrylates, Copovidone orMicrocrystalline Cellulose (MCC), alone or in combination.

According to an embodiment of the invention, the one or more binderscomprises one or more cellulose binders.

In an embodiment of the invention the one or more binders comprisesmicrocrystalline cellulose (MCC), hydroxypropyl cellulose (HPC) orhydroxypropylmethyl cellulose (HPMC) or any combination thereof.

In an embodiment of the invention the oral tablet compriseshydroxypropyl cellulose (HPC) binder in the amount of 0.1 to 6% byweight of the tablet, such as 0.1 to 5%, such as 0.1 to 4%, such as 0.1to 3%, such as 0.1 to 2% by weight of the tablet.

HPC may be applied as a particular attractive binder. Thus, this binder,when used with non-DC sugar alcohols such as erythritol, exhibits anadvantageous sensory experience when compared to other well-knownbinders, such as carboxymethylcellulose CMC. In particular, the usage ofHPC is lower than 4% by weight of the tablet is advantageous, such as0.1 to 3%, such as 0.1 to 2% by weight of the tablet.

In an embodiment of the invention the non-DC sugar alcohol particles areparticles that are not granulated, and the one or more binders arepresent as separate components in the tablet.

In an embodiment of the invention the non-DC sugar alcohol particles areparticles consisting of the sugar alcohol and the particles are notpre-granulated together with the one or more binders that are present inthe tablet as separate components.

It is noted that the use of binders as particles separate from thenon-DC sugar alcohol particles does not compromise the advantageoussensory properties even when applying a firm pressure tableting force,whereas the granulation with the binder to the sugar alcohol clearlyreduces the desired sensory properties.

High intensity artificial sweetening agents can also be used alone or incombination with the above sweeteners. Preferred high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, saccharin and its salts, cyclamic acid and itssalts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside(natural intensity sweetener) and the like, alone or in combination. Inorder to provide longer lasting sweetness and flavor perception, it maybe desirable to encapsulate or otherwise control the release of at leasta portion of the artificial sweeteners. Techniques such as wetgranulation, wax granulation, spray drying, spray chilling, fluid bedcoating, conservation, encapsulation in yeast cells and fiber extrusionmay be used to achieve desired release characteristics. Encapsulation ofsweetening agents can also be provided using another tablet componentsuch as a resinous compound.

Usage level of the artificial sweetener will vary considerably and willdepend on factors such as potency of the sweetener, rate of release,desired sweetness of the product, level and type of flavor used and costconsiderations. Thus, the active level of artificial sweetener may varyfrom about 0.001 to about 8% by weight (preferably from about 0.02 toabout 8% by weight). When carriers used for encapsulation are included,the usage level of the encapsulated sweetener will be proportionatelyhigher. Combinations of sugar and/or non-sugar sweeteners may be used inthe formulation.

In an embodiment of the invention, the tablet has a weight ratio betweensaid non-DC sugar alcohol particles and said DC sugar alcohol particles,which is between 0.3 and 1.2, such as between 0.5 and 1.2, such asbetween 0.7 and 1.1.

The weight ratio between non-DC sugar alcohol particles and DC sugaralcohol particles have proven significant according to an embodiment ofthe invention in the sense that a relatively high amount of non-DC sugaralcohol particles must be present in order to obtain the mouthfeel andtaste obtained through the invention. However, this taste and mouthfeelalso resides in the DC sugar alcohol particles. An example of such DCsugar alcohol particle is DC grade xylitol, which, together with thenon-DC sugar alcohol particles may provide a mouthfeel which is uniqueand very attractive to test panels.

The weight ratio between non-DC sugar alcohol particles and DC sugaralcohol particles have proven significant as mentioned above in relationto the direct sensation and mouthfeel experienced by the user but is hasmoreover addressed the challenge in relation to mouthfeel when DC sugaralcohol particles crumbles during the initial chew. The mechanicalstability of the tablet is much desired when the tablet is in itsnon-chewed form, but a fast disintegration and dissolving of a part ofthe tablet is desirable when the tablet is chewed due to the fact thatuser of the tablet dislike a sandy mouthfeel induced through smallhard-pressed crumbles of DC sugar alcohol. The use of a very high amountof non-DC sugar alcohol particles will facilitate a perceived fastdissolving and disintegration of a part of the tablet after the initialchews.

According to an embodiment of the invention the tablet has a weightratio between said non-DC sugar alcohol particles and said DC sugaralcohol particles, which is greater than 0.3, such as greater than 0.5,such as greater than 0.7.

According to an embodiment of the invention the tablet has a weightratio between said non-DC sugar alcohol particles and said DC sugaralcohol particles, which is smaller than 1.2, such as smaller than 1.1.

The weight ratio between non-DC sugar alcohol particles and DC sugaralcohol particles is important for the purpose of obtaining anadvantageous taste and mouthfeel. By having an upper limit of thisweight ratio, the chewer will moreover also experience a desirablecrunch sensation when starting masticating the tablet, the crunch beingobtained through the use of substantial amounts of DC sugar alcoholparticles and the non-DC sugar alcohol particles.

According to an embodiment of the invention, the tablet comprises thenon-DC sugar alcohol particles in an amount of greater than 0.3 gram.

According to an embodiment of the invention, the weight of non-DC sugaralcohol particles contained in the tablet is greater than greater than0.4 gram, such as greater than 0.5 gram, such as greater than 0.6 gram,such as greater than 0.7 gram, such as greater than 0.8 gram, such asgreater than 0.9 gram, such as greater than 1.0 gram.

According to a further embodiment of the invention, the amount of non-DCsugar alcohol particles is relatively high. It is in particular highwhen considering that the non-DC sugar alcohol in conventional sense isnot regarded attractive for compression, but the mouthfeel andsalivation perceived by the user is there improved significantly, whencompared to low amounts or the same amounts of DC sugar alcohol.

According to an embodiment of the invention, the tablet comprises thenon-DC sugar alcohol particles in an amount of less than 3.0 gram, suchas less than 2.0 gram, such as less than greater than 1.5 gram.

In an embodiment of the invention wherein the tablet has a weight ofbetween 0.5 and 4.0 grams.

In an embodiment of the invention, saliva generation upon mastication ofthe tablet is induced compared to a tablet without non-DC sugar alcoholparticles.

In an embodiment of the invention, saliva generation upon mastication ofthe tablet is induced compared to a tablet where the discrete areas arebased on DC sugar alcohol particles.

In an embodiment of the invention, the tablet generates more than 1.0 mLsaliva per 10 seconds within 30 seconds from onset of mastication.

In an embodiment of the invention, the tablet generates more than 0.5 mLsaliva per 10 seconds within a period from 30 to 90 seconds from onsetof mastication.

In an embodiment of the invention, the tablet generates more than 0.2 mLsaliva per 10 seconds within a period from 90 to 180 seconds from onsetof mastication.

In an embodiment of the invention, the tablet generates more than 0.2 mLsaliva per 10 seconds within a period from 180 to 300 seconds from onsetof mastication.

In an embodiment of the invention, the tablet comprises flavor.

The amount of flavor may e.g. be from 0.1 to about 10% by weight of thetablet, such as 0.1 to about 6% by weight of the tablet.

Usable flavors include almond, almond amaretto, apple, Bavarian cream,black cherry, black sesame seed, blueberry, brown sugar, bubblegum,butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake(graham crust), chili, cinnamon redhots, cotton candy, circus cottoncandy, clove, coconut, coffee, clear coffee, double chocolate, energycow, ginger, glutamate, graham cracker, grape juice, green apple,Hawaiian punch, honey, Jamaican rum, Kentucky bourbon, kiwi, koolada,lemon, lemon lime, tobacco, maple syrup, maraschino cherry, marshmallow,menthol, milk chocolate, mocha, Mountain Dew, peanut butter, pecan,peppermint, raspberry, banana, ripe banana, root beer, RY 4, spearmint,strawberry, sweet cream, sweet tarts, sweetener, toasted almond,tobacco, tobacco blend, vanilla bean ice cream, vanilla cupcake, vanillaswirl, vanillin, waffle, Belgian waffle, watermelon, whipped cream,white chocolate, wintergreen, amaretto, banana cream, black walnut,blackberry, butter, butter rum, cherry, chocolate hazelnut, cinnamonroll, cola, creme de menthe, eggnog, English toffee, guava, lemonade,licorice, maple, mint chocolate chip, orange cream, peach, pina colada,pineapple, plum, pomegranate, pralines and cream, red licorice, saltwater taffy, strawberry banana, strawberry kiwi, tropical punch, tuttifrutti, vanilla, or any combination thereof.

In an embodiment of the invention, the tablet comprises an activeingredient.

According to an embodiment of the invention the active ingredient isincluded in the population of particles.

In an embodiment of the invention, the tablet comprises an activepharmaceutical ingredient.

According to an embodiment of the invention the active pharmaceuticalingredient is included in the population of particles.

In an embodiment of the invention, the population of particles comprisesparticles comprising gum base, and wherein the tablet is designed to bemasticated into a coherent residual containing water-insolublecomponents.

The application of gum in the present context may invoke a delay ofrelease for active ingredients and this may again promote the buccal andupper throat absorption of active pharmaceutical ingredient when this isreleased from the oral tablet during mastication.

In an embodiment of the invention, the oral tablet contains particlescomprising gum base, and wherein the gum base comprises at least 5% byweight of elastomer.

The specific use of a relatively high proportion of elastomer in the gumbase may effectively be used for modification of the release of activeingredients in terms of time and amount and the elastomer may alsoprovide robust structure of the tablet facilitating that it is chewedinto a coherent residual containing water-insoluble components. Someactive ingredient may risk invoking disintegration of the residualwhereas an elastomer may increase the coherence and compensate for theaggressive active ingredients.

In an embodiment of the invention the gum base comprises at least 10% byweight of elastomer.

In an embodiment of the invention the gum base comprises at least 15% byweight of elastomer.

In an embodiment of the invention the gum base comprises between 15% and25% by weight of elastomer.

In an embodiment of the invention the gum base comprises between 17% and23% by weight of elastomer.

In an embodiment of the invention, one of the modules of the tablet isfree of gum base.

In an embodiment of the invention, the tablet is for use in buccalabsorption of active ingredients.

Moreover, the invention relates to a medical device in tablet formcomprising a population of particles, the population of particlescomprising a) directly compressible (DC) sugar alcohol particles, b)non-directly compressible (non-DC) sugar alcohol particles and c)particles comprising gum base, the medical device for use in thealleviation or treatment of xerostomia.

Moreover, the invention relates to a tablet form comprising a populationof particles, the population of particles comprising a) directlycompressible (DC) sugar alcohol particles, b) non-directly compressible(non-DC) sugar alcohol particles and c) particles comprising gum base,the medical device for use in treatment or alleviation of dysphagia.

The invention further relates to an oral delivery tablet suitable foractive pharmaceutical ingredients, the tablet comprising a) directlycompressible (DC) sugar alcohol particles and b) non-directlycompressible (non-DC) sugar alcohol particles comprised in a firstmodule and c) particles comprising gum base comprised in a secondmodule, the first module of the tablet being designed to turn intoliquid within 20 seconds of mastication.

The invention further relates to an oral delivery tablet suitable foractive pharmaceutical ingredients, the tablet comprising a) directlycompressible (DC) sugar alcohol particles and b) non-directlycompressible (non-DC) sugar alcohol particles comprised in a firstmodule and c) particles comprising gum base comprised in a secondmodule, the first module of the tablet being designed to dissolve within20 seconds of mastication.

Moreover, the invention relates to a method suitable for deliveringactive pharmaceutical ingredients, the method comprising the steps of:

-   -   i) providing an oral delivery tablet comprising a population of        particles, the population of particles comprising a) directly        compressible (DC) sugar alcohol particles, b) non-directly        compressible (non-DC) sugar alcohol particles and c) particles        comprising gum base, and    -   ii) masticating the tablet and thereby generating saliva in the        oral cavity induced by a plurality of discrete non-DC areas in        the tablet,    -   iii) obtaining by mastication a coherent residual containing        water-insoluble components from the tablet.

Moreover, the invention relates to a method of alleviating or treatingxerostomia, the method comprising the steps of:

-   -   i) providing an oral delivery tablet comprising a population of        particles, the population of particles comprising a) directly        compressible (DC) sugar alcohol particles, b) non-directly        compressible (non-DC) sugar alcohol particles and c) particles        comprising gum base, and    -   ii) masticating the tablet and thereby alleviating or treating        xerostomia.

Moreover, the invention relates to a method of alleviating or treatingof dysphagia, the method comprising the steps of:

-   -   i) providing an oral tablet comprising a population of        particles, the population of particles comprising a) directly        compressible (DC) sugar alcohol particles, b) non-directly        compressible (non-DC) sugar alcohol particles and c) particles        comprising gum base, and    -   ii) masticating the tablet into a coherent residual containing        water-insoluble components and thereby generating saliva in the        oral cavity,    -   iii) discarding the coherent residual containing water-insoluble        components.    -   iv) swallowing one or more pills together with induced saliva.

In an embodiment of the invention, the step ii) of masticating thetablet involves masticating the tablet and thereby promoting fastrelease of active ingredients induced by a plurality of discrete non-DCareas in the tablet.

In an embodiment of the invention, the step ii) of masticating thetablet involves masticating the tablet to release water solubleingredients into saliva induced by a plurality of discrete non-DC areasin the tablet.

In an embodiment of the invention, the step ii) of masticating thetablet involves releasing at least 50% by weight of the activeingredient within 20 seconds from onset of mastication.

In an embodiment of the invention, the oral tablet comprises an oralcare agent in the amount of at least 0.1% by weight of the oral tablet.

In an embodiment of the invention, the oral tablet comprises tooth pastein the amount of at least 0.1% by weight of the oral tablet.

In an embodiment of the invention the oral tablet comprises dentifricein the amount of at least 0.1% by weight of the oral tablet.

In an embodiment of the invention the oral tablet comprises dentifricein the amount of at least 0.1% to 25% by weight of the oral tabletexcluding abrasive.

Dentifrice will typically comprise at least one of the below activeingredients targeting oral care.

In an embodiment of the invention the active ingredient comprises one ormore oral care agents.

In an embodiment of the invention the active ingredient comprises one ormore anti-plaque agent.

Anti-plaque agents include fluoride ion sources. Anti-plaque agents areany substance which by itself acts to inhibit the accumulation ofbacterial deposits on the surfaces of the oral cavity. Examples includexylitol and other anti-microbial agents. The inhibition effects of thexylitol on oral microbes may have better effect when used in conjunctionwith an extract since the extract is also acting to disable themicrobes.

Typical examples of active ingredients that are particularly desirablefrom considerations of anti-plaque effectiveness, safety and formulationare:

-   -   Naficillin, oxacillin, vancomycin, clindamycin, erythromycin,        trimethoprim-sulphamethoxazole, rifampin, ciprofloxacin, broad        spectrum penicillin, amoxicillin, gentamicin, ceftriazoxone,        cefotaxime, chloramphenicol, clavunate, sulbactam, probenecid,        doxycycline, spectinomycin, cefixime, penicillin G, minocycline,        .beta.-lactamase inhibitors; meziocillin, piperacillin,        aztreonam, norfloxacin, trimethoprim, ceftazidime, dapsone.        Halogenated diphenyl ethers, e.g.        2′,4,4′-trichloro-2-hydroxydiphenyl ether (Triclosan),        2,2′-dihydroxy-5,5′-dibromo-diphenyl ether. Halogenated        salicylanilides, e.g. 4′,5-dibromosalicylanilide,        3,4′,5-trichloro-salicylanilide, 3,4′,5-tribromo-salicylanilide,        2,3,3′,5-tetrachloro-salicylanilide,        3,3,3′,5-tetrachloro-salicylanilide,        3,5-dibromo-3′-trifluoromethyl-salicylanilide,        5-n-octanoyl-3′-trifluoromethyl-salicylanilide,        3,5-dibromo-4′-trifluoromethyl-salicylanilide,        3,5-dibromo-3′-trifluoromethyl-salicylanilide (Flurophene).        Benzoic esters, e.g. methyl-p-hydroxybenzoic ester,        ethyl-p-hydroxybenzoic ester, propyl-p-hydroxybenzoic ester,        butyl-p-hydroxybenzoic ester. Halogenated carbanilides, e.g.        3,4,4′-trichlorocarbanilide,        3-trifluoromethyl-4,4′-dichlorocarbanilide, or        3,3,4′-trichlorocarbanilide. Phenolic compounds (including        phenol and its homologs, mono- and poly-alkyl and aromatic        halo-phenol and their homologs), e.g. phenol, 2-methyl-phenol,        3-methyl-phenol, 4-methyl-phenol, 4-ethyl-phenol,        2,4-dimethyl-phenol, 2,5-dimethyl-phenol, 3,4-dimethyl-phenol,        2,6-dimethyl-phenol, 4-n-propyl-phenol, 4-n-butyl-phenol,        4-n-amyl-phenol, 4-tert-amyl-phenol, 4-n-hexyl-phenol,        4-n-heptyl-phenol, 2-methoxy-4-(2-propenyl)-phenol (Eugenol),        2-isopropyl-5-methyl-phenol (Thymol), mono- and poly-alkyl- and        aralkyl-halophenols, methyl-p-chlorophenol, ethyl-p-chlorphenol,        n-propyl-p-chlorophenol, n-butyl-p-chlorophenol,        n-amyl-p-chlorophenol, sec-amyl-p-chlorophenol,        n-hexyl-p-chlorophenol, cyclohexyl-p-chlorophenol,        n-heptyl-p-chlorophenol, n-octyl-p-chlorophenol, o-chlorophenol,        methyl-o-chlorophenol, ethyl-o-chlorophenol,        n-propyl-o-chlorophenol, n-butyl-o-chlorophenol,        n-amyl-o-chlorophenol, tert-amyl-o-chlorophenol,        n-hexyl-o-chlorophenol, n-heptyl-o-chloropenol, p-chlorophenol,        o-benzyl-p-chlorophenol, o-benzyl-m-methyl-p-chlorophenol,        o-benzyl-m,m-dimethyl-p-chlorophenol,        o-phenylethyl-p-chlorophenol,        o-phenylethyl-m-methyl-p-chlorophenol, 3-methyl-p-chlorophenol,        3,5-dimethyl-p-chlorophenol, 6-ethyl-3-methyl-p-chlorophenol,        6-n-propyl-3-methyl-p-chlorophenol,        6-iso-propyl-3-methyl-p-chlorophenol,        2-ethyl-3,5-dimethyl-p-chlorophenol,        6-sec-butyl-3-methyl-p-chlorophenol,        2-iso-propyl-3,5-dimethyl-p-chlorophenol,        6-diethylmethyl-3-methyl-p-chlorophenol,        6-iso-propyl-2-ethyl-3-methyl-p-chlorophenol,        2-sec-amyl-3,5-dimethyl-p-chlorophenol,        2-diethylmethyl-3,5-dimethyl-p-chlorophenol,        6-sec-octyl-3-methyl-p-chlorophenol, p-bromophenol,        methyl-p-bromophenol, ethyl-p-bromophenol,        n-propyl-p-bromophenol, n-butyl-p-bromophenol,        n-amyl-p-bromophenol, sec-amyl-p-bromophenol,        n-hexyl-p-bromophenol, cyclohexyl-p-bromophenol, o-bromophenol,        tert-amyl-o-bromophenol, n-hexyl-o-bromophenol,        n-propyl-m,m-dimethyl-o-bromophenol, 2-phenyl-phenol,        4-chloro-2-methyl-phenol, 4-chloro-3-methyl-phenol,        4-chloro-3,5-dimethyl-phenol, 2,4-dichloro-3,5-dimethyl-phenol,        3,4,5,6-tetrabromo-2-methylphenol, 5-methyl-2-pentylphenol        4-isopropyl-3-methylphenol 5-chloro-2-hydroxydiphenyl-methane.        Resorcinol and its derivatives, e.g. resorcinol,        methyl-resorcinol, ethyl-resorcinol, n-propyl-resorcinol,        n-butyl-resorcinol, n-amyl-resorcinol, n-hexyl-resorcinol,        n-heptyl-resorcinol, n-octyl-resorcinol, n-nonyl-resorcinol,        phenyl-resorcinol, benzyl-resorcinol, phenylethyl-resorcinol,        phenylpropyl-resorcinol, p-chlorobenzyl-resorcinol,        5-chloro-2,4-dihydroxydiphenyl-methane,        4′-chloro-2,4-dihydroxydiphenyl-methane,        5-bromo-2,4-dihydroxydiphenyl-methane,        4″-bromo-2,4-dihydroxydiphenyl-methane. Bisphenolic compounds,        e.g. bisphenol A, 2,2′-methylene-bis-(4-chlorophenol),        2,2′-methylene-bis-(3,4,6-trichlorophenol) (hexachlorophene),        2,2′-methylene-bis-(4-chloro-6-bromophenol),        bis-(2-hydroxy-3,5-dichlorophenyl)-sulfide,        bis-(2-hydroxy-5-chlorobenzyl)-sulfide.

Illustrative of polyphosphate compounds with plaque-inhibitingproperties are dialkali metal and tetraalkali metal pyrophosphate andmixtures thereof in a hydrated or unhydrated form. Illustrative ofpyrophosphate salts are Na2H2P2O7, Na4P2O7 and K4P2O7. Other suitablepolyphosphates include hydrated or unhydrated alkali metaltripolyphosphates such as Na5P3O10 and K5P3O10.

In an embodiment of the invention the active ingredient comprises one ormore Anti-gingivitis agents.

Anti-gingivitis agents can be antiinflammatory agents, such as salicylicacid derivatives (e.g. aspirin), paraminophenol derivative (e.g.acetaminophen), indole and indene acetic acids (indo-methacin, sulindacand etodalac), heteroaryl acetic acids (tolmetin, diclofenac andketorolac), aryl propionic acid derivatives (ibuprofen, naproxen,ketoprofen, fenopren, oxaprozine), anthranilic acids-(mefenamic acid,meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazoneand oxyphenthatrazone), lactic acid bacteria (LAB), Osteopontin (ONP),IG-Lyt, hexefine, Aloe Vera, chlorhexedine, myrrh, or sage.

Anti-gingivitis agents also comprise psychotherapeutic agents, such asthorazine, serentil, mellaril, millazine, tindal, permitil, prolixin,trilafon, stelazine, suprazine, taractan, navan, clozaril, haldol,halperon, loxitane, moban, orap, risperdal, alprazolam, chlordiaepoxide,clonezepam, clorezepate, diazepam, halazepam, lorazepam, oxazepam,prazepam, buspirone, elvavil, anafranil, adapin, sinequan, tofranil,surmontil, asendin, norpramin, pertofrane, ludiomil, pamelor, vivactil,prozac, luvox, paxil, zoloft, effexor, welibutrin, serzone, desyrel,nardil, parnate, or eldepryl.

In an embodiment of the invention, the active ingredient comprises oneor more dental cosmetic ingredients.

A dental cosmetic ingredient includes a whitening agent. These areconveniently selected from teeth colour modifying substances that may beconsidered among the oral care actives useful in the oral tabletaccording to the invention. These substances are suitable for modifyingthe colour of the teeth to satisfy the consumer such as those listed inthe CTFA Cosmetic Ingredient Handbook, 3.sup.rd Edition, Cosmetic andFragrances Association Inc., Washington D.C. (1982), incorporated hereinby reference. Specific examples include talc, mica, magnesium carbonate,calcium carbonate, calcium pyrophosphate, Baking soda, Icelandic moss,bamboo, sodium hexametaphosphate, magnesium silicate, aluminiummagnesium carbonate, silica, titanium dioxide, zinc oxide, red ironoxide, brown iron oxide, yellow iron oxide, black iron oxide, ferricammonium ferrocyanide, manganese violet, ultramarine, nylon powder,polyethylene powder, methacrylate powder, polystyrene powder, silkpowder, crystalline cellulose, starch, titanated mica, iron oxidetitanated mica, bismuth oxychloride, and mixtures thereof. Typicallevels are from about 0.05% to about 20%, preferably from about 0.1% toabout 15% and most preferably from about 0.25% to about 10%, by weight,of the composition.

Whitening agents for use herein may also comprise materials that removeor bleach intrinsic or extrinsic stains on or in tooth surfaces. Suchsubstances are selected from the group consisting of the peroxides,metal chlorites, perborates, percarbonates, peroxyacids, persulphates,and combinations thereof. Suitable peroxide compounds include hydrogenperoxide, urea peroxide, calcium peroxide, carbamide peroxide andmixtures thereof. Suitable metal chlorites include calcium chlorite,barium chlorite, magnesium chlorite, lithium chlorite, sodium chloriteand potassium chlorite. Additional bleaching substances may behypochlorite, and chlorine dioxide. A preferred percarbonate is sodiumpercarbonate. Preferred persulphates are oxones. The content of thesesubstances is dependent on the available oxygen or chlorine.

In an embodiment of the invention the active ingredient comprises one ormore abrasives.

Within the scope of the invention, the oral tablet may compriseabrasive. Typical materials include silica gels and precipitates,aluminas, phosphates, and mixtures thereof. Specific examples includedicalcium orthophosphate dihydrate, calcium pyrophosphate, Bamboo,tricalcium phosphate, hydrated alumina, beta calcium pyrophosphate,calcium carbonate, sodium polymetaphosphate, sodium hexametaphosphate,Calgen, Giltex, Quadrafos, Hagan phosphate, micromet, calcium phosphatedibasic, calcium monohydrogen phosphate, dicalcium orthophosphatesecondary calcium phosphate, carbonic acid calcium salt, cacti,calcichew, calcidia, citrical, aragonite, calcite, valerite, aluminumoxide, alumina, silicon dioxide, silica, silicic anhydride, and resinousabrasive materials such as particulate condensation products of urea andformaldehyde and others such as disclosed in U.S. Pat. No. 3,070,510.Mixtures of polishing agents can also be used.

The silica polishing materials generally have an average particle sizeranging between about 0.1 to about 30 microns; and preferably from about5 to about 15 microns. The polishing agent can be precipitated silica orsilica gels, such as the silica xerogels described in U.S. Pat. No.3,538,230 or in U.S. Pat. No. 3,862,307. Preferred are the silicaxeropgels marketed under the name “Syloid” by the W. R. Grace andCompany, Davison Chemical Division. Also preferred are the precipitatedsilica materials such as those marketed by the J. M. Huber Corporationunder the trade name “Zeodent”, particularly the silica carrying thedesignation “Zeodent 119”. The types of silica dental polishing agentsuseful in the oral tablet of the present invention are described in moredetails in U.S. Pat. No. 4,340,583. The polishing agents in the oraltablet according to the invention is generally present in the range fromabout 6% to about 70%, preferably from about 10% to about 50%, by weightof the oral tablet.

In an embodiment of the invention the oral tablet comprises one of moreof the following active ingredients anti-plaque agent, anti-gingivitis,dental cosmetic ingredient and/or abrasive in the amount of 0.1% to 35%,such as from 1% to 25% or such as from about 5% to about 10%, by weightof the oral tablet.

The content of these oral care ingredients in the oral tablet accordingto the invention is generally in the range from about 0.1% to about 35%,preferably from about 1% to about 25% and most preferably from about 5%to about 10%, by weight of the oral tablet.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described with reference to the drawings where

FIGS. 1a and 1 b shows an embodiment of the invention,

FIGS. 2a and 2b shows a two-module version of an embodiment of theinvention,

FIGS. 3a and 3b shows a three-module version of an embodiment of theinvention,

FIGS. 4 and 5 illustrates embodiments of the invention and where

FIG. 6 illustrates a two-module version of an embodiment of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term “oral delivery tablet” is considered as a tabletfor oral use. The oral delivery tablet is considered as formed bytableting, i.e. compression of a particle composition, comprising thementioned population of particles. The oral delivery tablet is adelivery tablet in the sense that it is suitable for active ingredientsor active pharmaceutical ingredients. Attractive ingredients includecompounds for oral care or nutraceuticals. Nevertheless, the oraldelivery tablet may or may not comprise such active ingredients oractive pharmaceutical ingredients. Typically, the oral delivery tabletmay also be referred to as an oral tablet or merely a tablet.

Water-insoluble components in the present context typically refer toelastomer, natural or synthetic resins or other water-insolublecomponents such as water-insoluble softener or inorganic fillers.

As used herein, the phrase “tablet” refers to a tablet made bytabletting in a tabletting machine by pressing the tablet material toform the tablet. For example, the tablet material may be exposed to apunching means in a tableting machine, pressing e.g. granules and/orpowder to a gathered mass of pressed material.

In the present context the phrase “population of particles” refers to astatistical population of particles. The population of particles may becharacterized by a number of different parameters, e.g. statisticalparameters such as distribution of particles, average particle size,particle size distribution width, etc. The population of particles mayhave subpopulations, such as DC sugar alcohol particles, non-DC sugaralcohol particles, or in some embodiments particles comprising gum base.The phrasing “population of particles” may in an embodiment of theinvention be provided as a plurality of tableted particles and where thepopulation of particles are tableted in one module or it may refer to apopulation of particles where some of the particles are tableted intoone module and other particles are tableted into another module.

In the present context, the term “non-DC areas” refers to small volumesor spaces formed during tableting from the non-DC particles of non-DCsugar alcohol. Moreover, each of the non-DC areas may be composed of asingle non-DC sugar alcohol particle, or may comprise several non-DCsugar alcohol particles. When the non-DC areas are distinct, i.e. notdiffuse, the non-DC areas may be evenly distributed in the tablet, or atleast one module thereof when the tablet comprises two or more modules.In such embodiments, where the non-DC areas are evenly distributed in inthe tablet, or at least one module thereof, the non-DC areas may thusfacilitate an even saliva generation in the mouth upon mastication.

The term “non-DC sugar alcohol particles” refer to particles ofnon-directly compressible (non-DC) sugar alcohol. It is noted that theterms “non-DC sugar alcohol particles” and “non-DC particles” are usedinterchangeably. In the present context, the non-DC sugar alcoholparticles refer to particles which have not been preprocessed bygranulation with e.g. other sugar alcohols or binders for the purpose ofobtaining so-called direct compressible particles (DC). Thus, non-DCsugar alcohol particles are considered as particles consisting of non-DCsugar alcohol(s), often consisting of a single non-DC sugar alcohol.

The term “DC sugar alcohol particles” refer to particles of directcompressible (DC) sugar alcohol. It is noted that the terms “DC sugaralcohol particles” and “DC particles” are used interchangeably. DC sugaralcohol particles may be obtained e.g. as particles of sugar alcoholshaving DC grade by nature, e.g. sorbitol, or by granulating non-DC sugaralcohol with e.g. other sugar alcohols or binders for the purpose ofobtaining so-called direct compressible particles (DC).

In the present context when the non-DC areas are referred to as“discrete” this signifies that the non-DC sugar alcohols are notcontinuously distributed, but present in the discrete areascorresponding to the discrete nature of the non-DC sugar alcoholparticles.

In the present context, the term “suitable for active pharmaceuticalingredients” refers to the tablet as a suitable vehicle for e.g.inclusion and delivery of active pharmaceutical ingredients. However, itis noted that the tablet does not necessarily include activepharmaceutical ingredients or active ingredients.

The term “fast release” may in an embodiment refer to a large amount,such as at least 50% by weight of higher, of e.g. the active ingredientbeing released in a short time, such as within 20 seconds from onset ofmastication, or shorter.

When referring to induced saliva generation, it is noted that thisinduced saliva generation exceeds any saliva generation without the useof the tablet of the invention. Particularly, in an embodiment theinduced saliva generation exceeds saliva generation when usingconventional tablets without non-DC areas. Then, induced salivageneration is increased over any saliva generation associated withconventional products, e.g. by comparing with a tablet without non-DCsugar alcohol particles, or with a tablet where the discrete areas arebased on DC sugar alcohol particles.

When referring to induced saliva generation, the saliva generation maybe tested using the following method.

Test subjects abstain from eating and drinking at least 30 minutesbefore initiation of any test. Immediately before introducing of thetablet into the oral cavity, the test subject swallows. The test subjectrefrains from swallowing during the test. Immediately after introducingof the tablet into the oral cavity, the test subject starts masticatingthe tablet at a frequency of 1 chew per second for 30 seconds. 30seconds after starting the test, the test subject discards saliva into aplastic cup, which is weighted. The test subject keeps the coherentresidue in the mouth and continues chewing immediately after eachdiscarding of saliva. Saliva is discarded also at 90 seconds after onsetof mastication, at 180 seconds after onset of mastication, at 300seconds after onset of mastication, at 420 seconds after onset ofmastication, and at 600 seconds after onset of mastication. Salivageneration is noted as average amount of saliva per 10 seconds withinthe given time period.

As used herein, the term “particle size” refers to the average particlesize as determined according to European Pharmacopoeia 9.1 when usingtest method 2.9.38 particle size distribution estimation by analyticalsieving, unless otherwise specifically is mentioned.

In the present context, the term “taste masking” refers broadly tomasking of any sensations perceived as unpleasant or other off-notetastes, but not necessarily confined to the classical five basic tastes.A typical example of off-note taste includes bitter taste. Also,metallic taste is another example of as an off-note taste.

As used herein the term “active ingredient” refers to a substance thatis biologically active and has a physiological effect on the human bodyfor the benefit of the human body or part thereof. Active ingredientsinclude active pharmaceutical ingredients, but also other activesubstances such as nutraceuticals.

In the present context, the term “disintegrate” refers to is a processwhere a part or module of the tablet falls apart or disintegrates in tosmaller aggregates and as defined by European Pharmacopeia 2.9.1“Disintegration of tablets and capsules”. The time period of obtainingthe desired disintegration, here less than 20 seconds.

In the present context the term “release” refers to the releasedsubstance being liberated from the water-soluble matrix. In someembodiments, the process of releasing a substance corresponds to thesubstance being dissolved in saliva.

As used herein the term “buccal absorption” refers to a substancediffusing across the oral mucosa from the oral cavity to enter thebloodstream.

As used herein the term “oral mucosa” refers to the mucous membrane inthe oral cavity, i.e. in the mouth.

As used herein the term “gastrointestinal tract” refers to the part ofthe digestive system starting with the stomach and ending with therectum, including the intestines. Thus, the mouth and esophagus are notconsidered part of the gastrointestinal tract for the purposes of thepresent application.

As used herein the term “throat” is considered front part of the neck,positioned in front of the vertebra, and including the pharynx andlarynx.

The tabletting may be performed at a certain pressure, e.g. typicallydefined as compression force. Different types of tabletting machines areknown within the art, such as a rotary press device available by Fette.

As used herein, the phrase “granules” refers to entities made e.g. bygranulation, and may typically contain a plurality of particles adheredtogether.

By the phrase “texture” is meant a qualitative measure of thevisco-elastic properties of the tablet and of the overall mouth-feelexperienced by the user during the mastication process. Thus, the term“texture” encompasses measurable quantities such as hardness andelasticity as well as more subjective parameters related to thechew-feel experienced by a user.

In some embodiments of the present invention, the gum base componentscomprise for example

-   -   elastomer in the range of 1-15% by weight of the tablet,    -   natural and/or synthetic resin in the range of 5-35% by weight        of the tablet, and    -   further other gum base components in the range of 5-30% by        weight of the tablet.

It is evident, that the overall total amount of these above gum basecomponents must be mutually adjusted in order to fit requirements withrespect to tablet content of calcium carbonate, sweetener, flavor, etc.

In some embodiments of the present invention, the tablet comprisesnatural resins in an amount of 0.1 to 30%, such as 1 to 25%, such as 3to 25% or 5 to 25%, by weight of the tablet.

In some embodiments of the present invention, the tablet comprisesnatural resins in an amount of at least 10% by weight of the tablet.

In some embodiments of the present invention, the tablet is free ofnatural resins.

In embodiments of the present invention, the tablet comprises syntheticresins in an amount of 0.1 to 30%, such as 1 to 25%, such as 3 to 25% or5 to 25%, by weight of the tablet.

In embodiments of the present invention, the tablet comprises elastomerin an amount of at least 2% by weight of the tablet, such as at least 4%by weight of the tablet.

In embodiments of the present invention, the tablet comprises elastomerin an amount of less than 35% by weight of the tablet, such as less thanabout 25% by weight of the tablet, such as less than 20%, 15% or 10% byweight of the tablet.

In embodiments of the present invention, the tablet comprises one ormore flavoring agents, preferably in powdered form, selected from thegroup consisting of essential oils, essences, extracts, powders, acids,coconut, coffee, chocolate, vanilla, grape fruit, orange, lime, menthol,liquorice, caramel aroma, honey aroma, peanut, walnut, cashew, hazelnut,almonds, pineapple, strawberry, raspberry, apple, pear, peach, apricot,blackberry, cherry, pineapple, plum essence, clove oil, bay oil, anise,thyme, cedar leaf oil, nutmeg, cinnamon, peppermint, wintergreen,spearmint, eucalyptus, mint, or any combination thereof.

In embodiments of the present invention, the tablet is provided with acoating.

In embodiments of the present invention, the tablet has a weight in therange of 0.1 to 10 grams, such as in the range of 0.5 to 4 grams or suchas in the range of 1.5 to 2.5 grams.

According to an embodiment of the invention, the tablet may comprisefiller. In embodiments of the present invention, the tablet comprises anadditional filler in an amount of 0.1 to 40% by weight of the tablet.

Elastomers provide the rubbery, cohesive nature to the tablet, whichvaries depending on this ingredient's chemical structure and how it maybe compounded with other ingredients. Elastomers suitable for use in thetablet of the present invention may include natural or synthetic types.

Elastomer plasticizers vary the firmness of the gum base components.Their specificity on elastomer inter-molecular interaction(plasticizing) along with their varying softening points cause varyingdegrees of finished tablet firmness and compatibility with otheringredients. This may be important when one wants to provide moreelastomeric chain exposure to the alkane chains of the waxes. Theelastomer plasticizers may typically resins, such as synthetic resinsand/or natural resins.

The elastomers employed in the tablet may vary depending upon variousfactors such as the desired texture of the coherent residual (i.e. thetablet after mastication) and the other components used in theformulation to make the tablet. The elastomer may be any water-insolublepolymer known in the art. Illustrative examples of suitable polymers inthe tablet include both natural and synthetic elastomers. For example,those polymers which are suitable in the tablet include, withoutlimitation, natural substances (of vegetable origin) such as chicle gum,natural rubber, crown gum, nispero, rosidinha, jelutong, perillo, nigergutta, tunu, balata, guttapercha, lechi capsi, sorva, gutta kay, and thelike, and mixtures thereof. Examples of synthetic elastomers include,without limitation, styrene-butadiene copolymers (SBR), polyisobutylene,isobutylene-isoprene copolymers, polyethylene, and the like, andmixtures thereof.

Natural resins may be used according to the invention and may be naturalrosin esters (also known as ester gums), including as examples glycerolesters of partially hydrogenated rosins, glycerol esters of polymerizedrosins, glycerol esters of partially dimerized rosins, glycerol estersof tally oil rosins, pentaerythritol esters of partially hydrogenatedrosins, methyl esters of rosins, partially hydrogenated methyl esters ofrosins, pentaerythritol esters of rosins, synthetic resins such asterpene resins derived from alpha-pinene, beta-pinene, and/ord-limonene, and natural terpene resins.

In an embodiment of the invention a synthetic resin may includepolyvinyl acetate (PVA) and/or vinyl acetate-vinyl laurate (VA-VL)copolymers.

In an embodiment of the invention, the tablet may comprise one or morecomponents selected from the group consisting of bulk sweeteners,flavors, dry-binders, tabletting aids, anti-caking agents, emulsifiers,antioxidants, enhancers, absorption enhancers, high intensitysweeteners, softeners, colors, or any combination thereof.

In an embodiment of the invention, the tablet comprises, apart from theDC and non-DC sugar alcohol particles, sweeteners, such as bulksweeteners, sugar sweeteners, sugar substitute sweeteners, artificialsweeteners, high-intensity sweeteners, or any combination thereof.

Suitable bulk sweeteners include both sugar and non-sugar sweeteningcomponents.

Bulk sweeteners typically constitute from about 5 to about 95% by weightof the tablet, more typically about 20 to about 80% by weight such as 30to 70% or 30 to 60% by weight of the tablet.

Useful sugar sweeteners are saccharide-containing components commonlyknown in the tablet art including, but not limited to, sucrose,dextrose, maltose, lactose, dextrins, trehalose, D-tagatose, driedinvert sugar, fructose, levulose, galactose, corn syrup solids, and thelike, alone or in combination.

As an example, sorbitol can be used as a non-sugar sweetener. Otheruseful non-sugar sweeteners include, but are not limited to, other sugaralcohols such as mannitol, xylitol, maltitol, isomalt, erythritol,lactitol and the like, alone or in combination.

Applicable but non-limiting non-DC sugar alcohols to be used within thescope of the invention includes:

-   -   Non DC Xylitol: Xivia C from Dupont    -   Non DC Isomalt: Isomalt GS from Beneo Paltinit    -   Non DC Mannitol: Pearlitol from Roquette    -   Non DC Maltitol: Maltisorb. P200 from Roquette    -   Non DC Erythritol: Zerose 16952 from Cargill

High intensity artificial sweetening agents can also be used alone or incombination with the above sweeteners. For example, high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, saccharin and its salts, cyclamic acid and itssalts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside(natural intensity sweetener) and the like, alone or in combination. Inorder to provide longer lasting sweetness and flavor perception, it maybe desirable to encapsulate or otherwise control the release of at leasta portion of the artificial sweeteners. Techniques such as wetgranulation, wax granulation, spray drying, spray chilling, fluid bedcoating, conservation, encapsulation in yeast cells and fiber extrusionmay be used to achieve desired release characteristics. Encapsulation ofsweetening agents can also be provided.

Usage level of the artificial sweetener will vary considerably and willdepend on factors such as potency of the sweetener, rate of release,desired sweetness of the product, level and type of flavor used and costconsiderations. Thus, the active level of artificial sweetener may varyfrom about 0.001 to about 8% by weight (such as from about 0.02 to about8% by weight). When carriers used for encapsulation are included, theusage level of the encapsulated sweetener will be proportionatelyhigher. Combinations of sugar and/or non-sugar sweeteners may be used inthe tablet formulation.

A tablet according to the invention may, if desired, include one or morefillers/texturisers including as examples, magnesium, sodium sulphate,ground limestone, silicate compounds such as magnesium and aluminumsilicate, kaolin and clay, aluminum oxide, silicium oxide, talc,titanium oxide, mono-, di- and tri-calcium phosphates, cellulosepolymers, such as wood or microcrystalline cellulose (MCC), andcombinations thereof.

A number of further tablet materials well known within the art may beapplied within the scope of the present invention. Such componentscomprise but are not limited to waxes, fats, softeners, fillers,flavors, antioxidants, emulsifiers, colouring agents, binding agents andacidulants

The granules or some of the granules may for example consist or largelycomprise of gum base components and such granules may be manufactured bymeans of extrusion and under-water pelletizing.

According to the invention it is also possible to produce granulescomprising gum base with different average diameters by making granuleswith one diameter, and subsequently mix the granules with differentaverage diameters in desired proportions.

Although the openings of a die of an extruder device may havecross-sections of any desired shape, e.g. circular, oval, square etc.,it is in some embodiments preferred that the die device comprisesopenings with substantially circular cross-section and diameters in therange of 0.1 to 1.3 mm. A first set of openings can e.g. have a firstdiameter in the range of 0.07 to 0.7 mm, such as in the range of 0.15 to0.6 mm, and suitably in the range of 0.2 to 0.5 mm. A second set ofopenings can have a second diameter larger than said first diameter. Thesecond diameter is conveniently in the range of 0.4 to 1.3 mm, such asin the range of 0.7 to 1.2 mm.

In some embodiments the tablet granulating system further comprises adrying device. Powder sweetener or talk may be added to the granules ina final drying step. The drying device can be a conventional centrifugaldryer or another suitable dryer e.g. a fluid bed dryer. The dryingdevice can, for example, include a mixer. The powder sweetener may in anembodiment be sorbitol, which is mixed to the dried or partially driedgranules. Minor amounts of residual moisture on the surface of thegranules, e.g. 2% Wt. based on the total weight of the granules, maycontribute to the adherence of the sorbitol powder to the surface of thegranules. It is possible to use a conventional anti-agglomerating agentas e.g. talc, but sorbitol powder can function as an anti-agglomeratingagent, and at the same time serves as sweetener. Although sorbitol isfound to be most suitable, other bulk sweeteners based on polyols mayalso be suitable, e.g. mannitol, xylitol, hexa-resorcinol, maltitol,isomalt, erythriol, and lactitol.

In one embodiment the tablet granulating system according to theinvention further comprises one or more sieves adapted for removinggranules with an average diameter such as above 1.3 mm. The removal oflarger granules improves a subsequent tabletting process.

Examples of gum base components applicable for tablets of the presentinvention are described in the PCT/DK02/00461 and PCT/DK02/00462, herebyincorporated by reference.

The composition of gum base components, which are admixed with tabletingredients as defined below, can vary substantially depending on theparticular product to be prepared and on the desired masticatory andother sensory characteristics of the final product. However, typicalranges (weight %) of the above gum base components are:

-   -   elastomer in the range of 1-15% by weight of the tablet,    -   natural and/or synthetic resin in the range of 5-35% by weight        of the tablet, and    -   further other gum base components in the range of 5-30% by        weight of the tablet.

It is evident, that the overall total amount of these above gum basecomponents must be mutually adjusted in order to fit requirements withrespect to tablet content of calcium carbonate, sweetener, flavor, etc.

Granulates of gum base components may be manufactured according toconventional methods or e.g. those described in the PCT/DK02/00461 andPCT/DK02/00462, hereby incorporated by reference.

According to embodiments of the invention, encapsulated flavors oractive ingredients may be added to the final blend of raw materialsprior to compression.

Different methods of encapsulating flavors or active ingredients, whichmay both refer to flavors or active ingredients mixed into the rawmaterials to be compressed into the tablet may e.g. include spraydrying, spray cooling, film coating, coascervation, Double emulsionmethod (Extrusion technology) or prilling.

Materials to be used for the above-mentioned encapsulation methods maye.g. include Gelatine, Wheat protein, Soya protein, Sodium caseinate,Caseine, Gum arabic, Mod. starch, Hydrolyzed starches (maltodextrines),Alginates, Pectin, Carregeenan, Xanthan gum, Locus bean gum, Chitosan,Bees wax, Candelilla wax, Carnauba wax, Hydrogenated vegetable oils,Zein and/or Sucrose.

Preferably, these ingredients should be added subsequent to anysignificant heating or mixing. In other words, the active ingredientsshould preferably be added immediately prior to the compression of thefinal tablet.

In one embodiment, the adding of active ingredients may be cautiouslyblended with pre-mixed gum base granulates and further ingredients suchas the ingredients stipulated by the present claims, immediately priorto the final compression of the tablet.

For those active ingredients listed below, it should be noted that theyare optional in the present invention unless specifically stated.

In one embodiment the tablet according to the invention comprises apharmaceutically, cosmetically or biologically active substance.Examples of such active substances, a comprehensive list of which isfound e.g. in WO 00/25598, which is incorporated herein by reference,include drugs, dietary supplements, antiseptic agents, pH adjustingagents, anti-smoking agents and substances for the care or treatment ofthe oral cavity and the teeth such as hydrogen peroxide and compoundscapable of releasing urea during chewing. Examples of useful activesubstances in the form of antiseptics include salts and derivatives ofguanidine and biguanidine (for instance chlorhexidine diacetate) and thefollowing types of substances with limited water-solubility: quaternaryammonium compounds (e.g. ceramine, chloroxylenol, crystal violet,chloramine), aldehydes (e.g. paraformaldehyde), derivatives ofdequaline, polynoxyline, phenols (e.g. thymol, p-chlorophenol, cresol),hexachlorophene, salicylic anilide compounds, triclosan, halogenes(iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols(3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol,phenylethanol), cf. also Martindale, The Extra Pharmacopoeia, 28thedition, pages 547-578; metal salts, complexes and compounds withlimited water-solubility, such as aluminum salts, (for instance aluminumpotassium sulphate AlK(SO4)2, 12H2O) and salts, complexes and compoundsof boron, barium, strontium, iron, calcium, zinc, (zinc acetate, zincchloride, zinc gluconate), copper (copper chloride, copper sulphate),lead, silver, magnesium, sodium, potassium, lithium, molybdenum,vanadium should be included; other compositions for the care of mouthand teeth: for instance; salts, complexes and compounds containingfluorine (such as sodium fluoride, sodium monofluorophosphate,aminofluorides, stannous fluoride), phosphates, carbonates and selenium.Further active substances can be found in J. Dent. Res. Vol. 28 No. 2,pages 160-171,1949.

Examples of active substances in the form of agents adjusting the pH inthe oral cavity include: acids, such as adipic acid, succinic acid,fumaric acid, or salts thereof or salts of citric acid, tartaric acid,malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acidand acceptable bases, such as carbonates, hydrogen carbonates,phosphates, sulphates or oxides of sodium, potassium, ammonium,magnesium or calcium, especially magnesium and calcium.

Active ingredients may comprise the below mentioned compounds orderivates thereof but are not limited thereto: Acetaminophen,Acetylsalicylic acid, Buprenorphine, Bromhexin, Celcoxib, Codeine,Diphenhydramin, Diclofenac, Etoricoxib, Ibuprofen, Indometacin,Ketoprofen, Lumiracoxib, Morphine, Naproxen, Oxycodon, Parecoxib,Piroxicam, Pseudoefedrin, Rofecoxib, Tenoxicam, Tramadol, Valdecoxib,Calciumcarbonat, Magaldrate, Disulfiram, Bupropion, Nicotine,Azithromycin, Clarithromycin, Clotrimazole, Erythromycin, Tetracycline,Granisetron, Ondansetron, Prometazin, Tropisetron, Brompheniramine,Ceterizin, leco-Ceterizin, Chlorcyclizine, Chlorpheniramin,Chlorpheniramin, Difenhydramine, Doxylamine, Fenofenadin, Guaifenesin,Loratidin, des-Loratidin, Phenyltoloxamine, Promethazin, Pyridamine,Terfenadin, Troxerutin, Methyldopa, Methylphenidate, Benzalcon.Chloride, Benzeth. Chloride, Cetylpyrid. Chloride, Chlorhexidine,Ecabet-sodium, Haloperidol, Allopurinol, Colchinine, Theophylline,Propanolol, Prednisolone, Prednisone, Fluoride, Urea, Actot,Glibenclamide, Glipizide, Metformin, Miglitol, Repaglinide,Rosiglitazone, Apomorfin, Cialis, Sildenafil, Vardenafil, Diphenoxylate,Simethicone, Cimetidine, Famotidine, Ranitidine, Ratinidine, cetrizin,Loratadine, Aspirin, Benzocaine, Dextrometorphan, Phenylpropanolamine,Pseudoephedrine, Cisapride, Domperidone, Metoclopramide, Acyclovir,Dioctylsulfosucc., Phenolphtalein, Almotriptan, Eletriptan, Ergotamine,Migea, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan, Aluminumsalts, Calcium salts, Ferro salts, Ag-salts, Zinc-salts, Amphotericin B,Chlorhexidine, Miconazole, Triamcinolonacetonid, Melatonine,Phenobarbitol, Caffeine, Benzodiazepiner, Hydroxyzine, Meprobamate,Phenothiazine, Buclizine, Brometazine, Cinnarizine, Cyclizine,Difenhydramine, Dimenhydrinate, Buflomedil, Amphetamine, Caffeine,Ephedrine, Orlistat, Phenylephedrine, Phenylpropanolamin,Pseudoephedrine, Sibutramin, Ketoconazole, Nitroglycerin, Nystatin,Progesterone, Testosterone, Vitamin B12, Vitamin C, Vitamin A, VitaminD, Vitamin E, Pilocarpin, Aluminumaminoacetat, Cimetidine, Esomeprazole,Famotidine, Lansoprazole, Magnesiumoxide, Nizatide and or Ratinidine.

The invention is suitable for increased or accelerated release of activeagents selected among the group of dietary supplements, oral and dentalcompositions, antiseptic agents, pH adjusting agents, anti-smokingagents, sweeteners, flavorings, aroma agents or drugs. Some of thosewill be described below.

The active agents to be used in connection with the present inventionmay be any substance desired to be released from the tablet. The activeagents, for which a controlled and/or accelerated rate of release isdesired, are primarily substances with a limited water-solubility,typically below 10 g/100 ml inclusive of substances which are totallywater-insoluble. Examples are medicines, dietary supplements, oralcompositions, anti-smoking agents, highly potent sweeteners, pHadjusting agents, flavorings etc.

Other active ingredients are, for instance, paracetamol, benzocaine,cinnarizine, menthol, carvone, caffeine, chlorhexidine-di-acetate,cyclizine hydrochloride, 1,8-cineol, nandrolone, miconazole, mystatine,sodium fluoride, nicotine, cetylpyridinium chloride, other quaternaryammonium compounds, vitamin E, vitamin A, vitamin D, glibenclamide orderivatives thereof, progesterone, acetylsalicylic acid, dimenhydrinate,cyclizine, metronidazole, sodium hydrogen carbonate, the activecomponents from ginkgo, the active components from propolis, the activecomponents from ginseng, methadone, oil of peppermint, salicylamide,hydrocortisone or astemizole.

Examples of active agents in the form of dietary supplements are forinstance salts and compounds having the nutritive effect of vitamin B2(riboflavin), B12, folinic acid, folic acid, niacine, biotine, poorlysoluble glycerophosphates, amino acids, the vitamins A, D, E and K,minerals in the form of salts, complexes and compounds containingcalcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese,chromium, selenium, molybdenum, potassium, sodium or cobalt.

Furthermore, reference is made to lists of nutritionists accepted by theauthorities in different countries such as for instance US code ofFederal Regulations, Title 21, Section 182.5013.182 5997 and182.8013-182.8997.

Examples of active agents in the form of compounds for the care ortreatment of the oral cavity and the teeth are for instance boundhydrogen peroxide and compounds capable of releasing urea duringchewing.

Examples of active agents in the form of antiseptics are for instancesalts and compounds of guanidine and biguanidine (for instancechlorhexidine diacetate) and the following types of substances withlimited water-solubility: quaternary ammonium compounds (for instanceceramine, chloroxylenol, crystal violet, chloramine), aldehydes (forinstance paraformaldehyde), compounds of dequaline, polynoxyline,phenols (for instance thymol, para chlorophenol, cresol)hexachlorophene, salicylic anilide compounds, triclosan, halogenes(iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols(3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol,phenylethanol), cf. furthermore Martindale, The Extra Pharmacopoeia,28th edition, pages 547-578; metal salts, complexes and compounds withlimited water-solubility, such as aluminum salts, (for instance aluminumpotassium sulphate AlK(SO4)2,12H2O) and furthermore salts, complexes andcompounds of boron, barium, strontium, iron, calcium, zinc, (zincacetate, zinc chloride, zinc gluconate), copper (copper chloride, coppersulfate), lead, silver, magnesium, sodium, potassium, lithium,molybdenum, vanadium should be included; other compositions for the careof mouth and teeth: for instance; salts, complexes and compoundscontaining fluorine (such as sodium fluoride, sodiummonofluorophosphate,amino fluorides, stannous fluoride), phosphates, carbonates andselenium.

Cf. furthermore J. Dent. Res. Vol. 28 No. 2, pages 160-171, 1949,wherein a wide range of tested compounds is mentioned.

Examples of active agents in the form of agents adjusting the pH in theoral cavity include for instance: acceptable acids, such as adipic acid,succinic acid, fumaric acid, or salts thereof or salts of citric acid,tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid andglutaric acid and acceptable bases, such as carbonates, hydrogencarbonates, phosphates, sulfates or oxides of sodium, potassium,ammonium, magnesium or calcium, especially magnesium and calcium.

Examples of active agents in the form of anti-smoking agents include forinstance: nicotine, tobacco powder or silver salts, for instance silveracetate, silver carbonate and silver nitrate.

In a further embodiment, the sucrose fatty acid esters may also beutilized for increased release of sweeteners including for instance theso-called highly potent sweeteners, such as for instance saccharin,cyclamate, aspartame, thaumatin, dihydrocalcones, stevioside,glycyrrhizin or salts or compounds thereof. For increased released ofsweetener, the sucrose fatty acids preferable have a content ofpalmitate of at least 40% such as at least 50%.

Further examples of active agents are medicines of any type.

Examples of active agents in the form of medicines include caffeine,salicylic acid, salicyl amide and related substances (acetylsalicylicacid, choline salicylate, magnesium salicylate, sodium salicylate),paracetamol, salts of pentazocine (pentazocine hydrochloride andpentazocinelactate), buprenorphine hydrochloride, codeine hydrochlorideand codeine phosphate, morphine and morphine salts (hydrochloride,sulfate, tartrate), methadone hydrochloride, ketobemidone and salts ofketobemidone (hydrochloride), beta-blockers, (propranolol), calciumantagonists, verapamil hydrochloride, nifedinpine as well as suitablesubstances and salts thereof mentioned in Pharm. Int., Nov. 85, pages267-271, Barney H. Hunter and Robert L. Talbert, nitroglycerine,erythrityl tetranitrate, strychnine and salts thereof, lidocaine,tetracaine hydrochloride, etorphine hydrochloride, atropine, insulin,enzymes (for instance papain, trypsin, amyloglucosidase, glucoseoxidase,streptokinase, streptodornase, dextranase, alpha amylase), polypeptides(oxytocin, gonadorelin, (LH.RH), desmopressin acetate (DDAVP),isoxsuprine hydrochloride, ergotamine compounds, chloroquine (phosphate,sulfate), isosorbide, demoxytocin, heparin.

Other active ingredients include beta-lupeol, Letigen®, Sildenafilcitrate and derivatives thereof.

Dental products include Carbamide, CPP Caseine Phosphor Peptide;Chlorhexidine, Chlorhexidine di acetate, Chlorhexidine Chloride,Chlorhexidine di gluconate, Hexetedine, Strontium chloride, PotassiumChloride, Sodium bicarbonate, Sodium carbonate, Fluor containingingredients, Fluorides, Sodium fluoride, Aluminum fluoride.

Ammonium fluoride, Calcium fluoride, Stannous fluoride, Other fluorcontaining ingredients Ammonium fluorosilicate, Potassiumfluorosilicate, Sodium fluorosilicate, Ammonium monofluorphosphate,Calcium monofluorphosphate, Potassium monofluorphosphate, Sodiummonofluorphosphate, Octadecentyl Ammonium fluoride, StearylTrihydroxyethyl Propylenediamine Dihydrofluoride,

Vitamins include A, B1, B2, B6, B12, Folinic acid, Folic acid, niacin,Pantothenic acid, biotine, C, D, E, K. Minerals include Calcium,phosphor, magnesium, iron, Zinc, Cupper, Iod, Mangan, Crom, Selene,Molybden. Other active ingredients include:

-   -   Q100, enzymes. Natural drugs including Ginkgo Biloba, ginger,        and fish oil.

The invention also relates to use of migraine drugs such as Serotoninantagonists: Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan,Eletriptan; nausea drugs such as Cyclizin, Cinnarizin, Dimenhydramin,Difenhydrinat; hay fever drugs such as Cetrizin, Loratidin, pain reliefdrugs such as Buprenorfin, Tramadol, oral disease drugs such asMiconazol, Amphotericin B, Triamcinolonaceton; and the drugs Cisaprid,Domperidon, Metoclopramid. In a preferred embodiment the inventionrelates to the release of Nicotine and its salts.

The following non-limiting examples illustrate different variations ofthe present invention. The examples are meant for indicating theinventive concept; hence the mentioned examples should not be understoodas exhaustive for the present invention.

FIGS. 1a and 1b illustrates an embodiment of an oral tablet 10 accordingto an embodiment of the invention. FIG. 1a shows the oral tablet fromthe side and FIG. 1b shows the tablet from above.

The composition and the way the tablet is or can be made is describedelsewhere in the application and details regarding the structure andfunctioning of this tablet 10 is also indicated and explained furtherwith reference to FIG. 4 and FIG. 5.

FIGS. 2a and 2b illustrates a two-module version of an oral tabletaccording to an embodiment of the invention. FIG. 2a shows the oraltablet from the side and FIG. 2b shows the tablet from above.

The composition and the way the tablet is made is described elsewhere inthe application.

Details regarding the structure and functioning of this tablet 10 isalso indicated and explained further with reference to FIGS. 4, 5 and 6.

The intention with this illustration is to give an example of a physicalform, which may be applicable within the scope of the invention. Theintention is also to illustrate how the term “a module” is understoodand applied throughout the description, i.e. that a module is referringto a population of a plurality particles and the particles have beentableted together to form a module. The term module is applied toindicate that one module comprises one population of tableted particlesand another module comprises another population of tableted particles. Apopulation of particles in the present context is thus understood torefer to a plurality of particles. A singular particle is thus of coursenot understood as a module.

Modules are typically, but not necessarily, distinguishable by the humaneye, in particular if the applied compounds in the different modules areformed by differently colored population of particles or mixtures ofparticles.

The oral tablet 20 comprises an upper module 21 and a lower module 22.The modules, here in the shapes of layers, are thus physically distinctand each comprises a population of particles which has been tableted.The population of the different modules, 21 and 22, may typically bedifferent for many purposes. Examples include use for visual conception,for mechanical purposes e.g. providing strength, for medical purposes,and of course also for maximizing the desired effect of non-DC sugaralcohol contained in the tablet.

In a preferred embodiment, most of the applied non-DC sugar alcohol(s)is comprised in the upper module 21 and the lower module 22 is mostlycomprised of DC-components, i.e. components such as sugar alcohols,fillers, flavors, colors etc. conventionally used for directcompression. In embodiments of the invention, a first module, here thelower module 22 may be regarded and applied as a support modulesupporting another module, here the upper module 21. The benefit of thisdivision in the designing of properties is that the module containingthe non-DC sugar alcohol particles may comprises substantial amounts ofnon-DC sugar alcohol particles even in spite of the fact that themodules own mechanical strength is substantially weakened, as thesupporting modules structural strength may be designed to ensure thatthe overall structural strength of the tablet is sufficient to obtainthe desired friability and tablet appearance. This multi-modular designapproach is of even more interest as the tablets designed according tothis principle benefits, in terms of disintegration and dissolving ofthe tablet matrix or part thereof during mastication of the tablet, fromthe increased salivation effect obtained from the applied high contentof non-DC sugar alcohol particles in the relatively weak module.

FIGS. 3a and 3b illustrates a three-module version of an oral tablet 30according to an embodiment of the invention. FIG. 3a shows the oraltablet 30 from the side and FIG. 3b shows the tablet from above.

The illustrated tablet 30 comprises an upper module 31, and intermediatemodule 33 and a lower module 32.

The upper module 31 may, as explained in relation to the upper module ofFIGS. 2a and 2b , be formed by a population of particles comprising aneffective amount of non-DC sugar alcohol particles. The intermediatelayer may comprise further non-DC sugar alcohol particles and or adesired active ingredient.

The lower module 32 may comprise substantial amounts of DC-particlessuch as sugar alcohol(s), fillers, some binder and other relevantingredients enabling the lower module 32 to form a structural supportfor at least the upper module 31.

FIG. 4 illustrates a part 40 of a cross-section of one of the oraltablets in FIG. 1-3. The part of the oral tablet, illustrated in FIG. 4may thus correspond to a view of a part of the upper layers 21 or 31 ora part of the tablet 1.

Such part 40 of a tablet may within the scope of the invention compriseat least two different types of particles, namely non-DC sugar alcoholparticles 41 and DC-particles 42. Preferred but non-limiting non-DCsugar alcohols are non-DC erythritol and non-DC xylitol as these non-DCsugar alcohols have shown effective to obtain the desired effect. Theillustrated non-DC particles 41, although indicated on the figures withthe same graphical expression may of course comprise non-DC sugaralcohol particles of the same type, but also comprise a mixture of twoor more non-DC sugar alcohol particles.

The particles are evenly distributed amongst a plurality of DC particles42 within the specified module. The DC particles 42, although indicatedin the figure as same type particles may include different types of DCsugar alcohol particles, flavor particles, binders, etc. The intentionwith the figure is to illustrate that the non-DC sugar alcohol particles41 in practice have to be homogenously distributed amongst the DCparticles 42 in the final oral tablet 40. It may not be enough that thenon-DC particles and DC particles are mixed homogenously at some stageduring the preparation of the tableting process. The homogenous mixshould preferably be maintained in the final oral tablet 40 in order topromote the desired effect and to obtain a mechanically stable tablet. Afurther advantageous effect of the evenly distributed non-DC sugaralcohol particles may be obtained through an advantageous and increasedsalivation during mastication of a tablet.

The understanding and conception of the evenly distribution of thenon-DC sugar alcohol particles in the relevant tablet module may inpractical terms be very difficult to define as such definitions are verydifficult to monitor and control during the processing of the tablet butit has been possible to establish an industrial scale process, where themixture containing the substantial amounts of non-DC sugar alcohol(s)may be established all the way through the process into the finaltablet. Such process may e.g. be validated by test manufacturing of asequence of tablets where the variation of the non-DC sugar alcoholcontent of the manufactured tablets are determined.

It is noted that the non-DC particles 41 forms small sub-areas or subspaces in the final oral tablet or the relevant module of the finaltablet, e.g. the upper modules 21 and 31. These sub-areas are elsewherein the present application referred to as discrete non-DC areas and maybe formed by single non-DC particles or very small groups of thesenon-DC particles. These discrete non-DC areas are thus intended to becontained within a matrix formed by DC-sugar alcohol particles or otherDC-particles.

The non-DC areas, in the present embodiment, the non-DC sugar alcoholparticles 41 are thus included in substantial amounts in the tablet andfrom a mechanical perspective supported and contained by theDC-particles 42 and together forming a matrix which, when chewed, maybring the non-DC sugar alcohol particles 41 into contact with the oralcavity and promote salivation. The promoted salivation, together withrelatively weak mechanical structure of the module or tablet comprisingthe non-DC sugar alcohol particles induces a fast breakup of the tabletand thereby pushes the non-DC particles into contact with the oralcavity in a way which is completely different from compressed tabletsmade from DC-sugar alcohol particles, such as granulated erythritol orxylitol.

The non-DC areas may thus result in induced saliva generation uponmastication of the tablet and also induce and promote a very fast andpleasant dissolving of the tablet matrix or part thereof when comparedto conventional compressed tablets.

Active ingredients may be present as both DC and non-DC particles aslong as the active ingredient as such does not interfere significantwith other compounds. If the active ingredients are non-DC particles,the amount should be kept low enough to ensure the mechanical stabilityof the tablet or modules or alternatively compensated by relevantDC-particles or binders. It should be noted that such a compensationshould be carefully considered as this compensation may both compromisesalivation effect and texture/mouthfeel during mastication.

FIG. 5 illustrates a part of a cross-section of one of the oral tabletsin FIG. 1-3. The part of the oral tablet, illustrated in FIG. 5 may thuscorrespond a view of a part of the upper modules 21 or 31 or the tablet1.

In terms of components applied, the tablet part illustrated in FIG. 5may largely correspond to the above-described embodiment of FIG. 4, butnow the tablet part comprises larger sized non-DC particles 51containing in a compression of particles of DC particles 52.

The intention with the present FIG. 5 is merely to indicate that inparticular the non-DC sugar alcohol particles may be larger in size thanthe DC particles and it is also noted in this context that the use oflarger sized non-DC sugar alcohol particles may indeed increase theobtained salivation or the desired effect.

FIG. 6 illustrates a particular transition in a tablet 60 with twoadjacent modules according to an embodiment of the invention. Thepresently illustrated part of such tablet may e.g. refer to thetransition between the modules 21 and 22 of the tablet 20 as seen inFIG. 2a . The tablet 60 comprises non-DC sugar alcohol particles 61 andDC particles 62 in one module and another module comprising DC particles63. The understanding of a module is here easily conceivable as thepopulation of non-DC sugar alcohol particles 61 and DC particles 62forms one module and the population of DC particles 63 forms anothermodule. Often, the compositions of the DC sugar alcohol particles 62 andthe DC sugar alcohol particles 63 may be different, depending on thespecific circumstances.

In the present context, the tablet comprises particles comprising gumbase. Thus, when the particles 42, 52 62, 63 above are described as DCsugar alcohol particles, it is merely for illustrative purposes, andcould also comprise e.g. a mixture of DC sugar alcohol particles andparticles comprising gum base.

Again, in relation to FIG. 5 and FIG. 6, active ingredients may bepresent as both DC and non-DC particles as long as the active ingredientas such does not interfere significant with other compounds. If theactive ingredients are non-DC particles, the amount should be kept lowenough to ensure the mechanical stability of the tablet or modules oralternatively compensated by relevant DC-particles or binders. It shouldbe noted that such a compensation should be carefully considered as thismay compensation may both compromise salivation effect andtexture/mouthfeel during mastication.

Particles comprising gum base, may also be present both as non-DC and DCparticles, although DC-particles comprising gum base are highlypreferred over non-DC gum base-containing particles. When applyingparticles comprising gum base, these particles are preferably but notnecessarily included in a supporting module as DC particles 63 e.g. withmixed with sugar alcohol particles 63 as illustrated in FIG. 6.

The above illustrated modules are all designed as layers. It is stressedthat other shapes of modules may be applicable within the scope of theinvention. Non-limiting examples are modules having a sphere shape,diamond shape, oval shape, cone shape, etc. All the relevant shapes mustof course be adapted to fit the tableting process according to knownmeasures within the art.

EXAMPLES Examples 1-7. Gum Bases

Seven different samples, given samples numbers 101-107, of gum bases areprovided in Examples 1-7. The compositions are given in table 1 and thesamples were prepared by the following process:

Elastomers and about ⅓ of the resin are mixed at 120° C. together withfiller in a pre-heated mixer having horizontally placed Z-shaped armsfor mixing. The fillers are talc or non-DC calcium carbonate. Themechanical action of the mixer causes shearing and grinding resulting insoftening of the elastomers.

When the elastomers are softened, more resin is slowly added to theelastomer, resin and filler until the mixture becomes homogeneous. Theremaining resin is then added to the mixer and mixed for 10-20 minutes.The softeners, i.e. emulsifier, wax and vegetable fat, are then addedand mixed for 20-40 minutes until the whole mixture becomes homogeneous.

After a total mixing time of about 45-60 minutes, the mixture issubjected to pelletizing in a standard under water pelletizing (UWP)unit resulting in coherent granules with an average diameter ofapproximately 1 mm.

The applied polyisobutylene may eg. be Oppanol B12, polyvinyl acetate(PVA) may eg. be Vinnapas B 1.5 sp, VA-VL copolymers (vinylacetate-vinyl laurate copolymers) may eg. be Vinnapas B 500/20 VL,natural resin may eg. be Staybelite 5E or Piccolyte C85, softener mayeg. be hydrogenated vegetable fat such as hydrogenated sunflower oil,Bulk sweetener may eg. be sorbitol, flavor may eg. be menthol crystals.It is stressed that the specifically mentioned components are of coursea non-limiting disclosure intended to assist a skilled person inreproducing the present invention.

In case of Example 7 (sample no. 107), the homogeneous mixture is notsubjected to pelletizing but merely discharged into a pan and allowed tocool to room temperature.

Then the mixture is added to another mixer having horizontally placedZ-shaped arms for mixing operating at a temperature of about 40° C. Bulksweetener is added and mixed until a homogenous mass is obtained.

The mass is discharged and cooled by liquid nitrogen before beingintroduced to a milling device, in which the mass is milled to obtainparticulate material that is ready for tableting.

TABLE 1 Numbers are given in percent by weight of the gum base Gum baseEx. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Sample no. 101 102 103 104 105106 107 Elastomers (butyl 18 21 21 10 10 5 16 rubber andpolyisobutylene) Resins (polyvinyl 38 44 44 50 50 55 31 acetate (PVA),VA-VL copolymers and natural resins (ester gums and terpene resins)Softeners (wax, fats, 23 21 21 22 23 20 19 emulsifiers) Filler (talc) 1811 17 20 14 Filler (Calcium 12 15 carbonate) Bulk sweetener 20 Flavor 33 2 3 Total 100 100 100 100 100 100 100

Example 8-22 Preparation of Tablets

Tablets according to Examples 8-22 using the compounds as outlined belowin Table 2, Table3 and Table 4 were prepared as follows:

The compounds of Examples 1-7 are present in the form ofparticles/granules.

The particulate compounds of Examples 1-7 and further tablet compoundsare weighed into the proper amounts according to the exampledcompositions of Table 2 to Table 4.

The weighed amounts are then added to a Turbula mixer in a stainlesssteel container and blended at 50 rpm for 4 minutes and then addingmagnesium stearate and blending one additional minute.

The mixtures are then tableted by means of a Piccola RIVA DC-SC-041-2. AFette 3090i may also be used.

The resulting tablets according to Examples 8-22 are then obtained bytableting with a suitable pressure force.

For each tablet of examples 8-22, the second layer as outlined in Table2, Table 3 and Table 4 is pressed initially at a first relatively lowpressure. The blended composition of the so-called first layer, i.e.compositions of Table 2 to 4 is then fed to the mold and a finaltwo-layer tablet is then compressed at higher pressure than the pressureapplied on the first layers, thereby producing final two-layer tabletsaccording to Examples 8-17. It is noted that the final two-layer tabletsof the present examples are 2.0 gram tablets and that the first layer ofthe tablets weighs 0.9 gram and the second layer of the tablets weighs1.1 gram.

TABLE 2 Numbers are given in percent by weight of each layer of thetablet Ex8 Ex 9 Ex 10 Ex 11 Ex 12 Raw material (wt %) First layer Non-DC48 48 50 50 48 Erythritol DC Isomalt 47.75 45.75 43.75 41.75 Sorbitol —— — — 48.75 Flavor 2 2 4 4 2 HIS 0.25 0.25 0.25 0.25 0.25 Magnesium 1 11 1 1 Stearate Binder HPC 1 3 1 3 — Raw material (wt %) Second layer Gumbase 30 20 10 40 30 sample no. 101 Gum base 10 20 30 0 10 sample no. 102DC Xylitol 27.50 27.75 — — 54.50 Non-DC Xylitol 27 27 — — — DC Isomalt —— 27.50 27.75 — Non DC Isomalt — — 27 27 — Salivation flavor 0.25 — 0.25— 0.25 Flavor 4 4 4 4 4 HIS 0.25 0.25 0.25 0.25 0.25 Magnesium 1 1 1 1 1Stearate Friability % 2.9 1.7 2.76 1.58 0.77

TABLE 3 Examples with different types of active ingredients. Numbers aregiven in percent by weight of each layer of the tablet Ex13 Ex 14 Ex 15Ex 16 Ex 17 Raw material (wt %) First layer Non-DC 48 48 48 48 48Erythritol DC Isomalt 47.75 47.75 27.75 47.75 47.75 Flavor 2 2 2 2 2 HIS0.25 0.25 0.25 0.25 0.25 Magnesium 1 1 1 1 1 Stearate Binder HPC 1 1 1 11 DC CaCO3 20 Raw material (wt %) Second layer Gum base 20 20 20 20 20sample no. 101 Gum base 20 20 20 20 20 sample no. 102 DC Xylitol 27.5522.75 27.75 26.75 27.25 Non-DC Xylitol 27 27 27 27 27 Flavor 4 4 4 4 4HIS 0.25 0.25 0.25 0.25 0.25 Magnesium 1 1 1 1 1 Stearate Nicotine 0.2Caffeine 5 Bromhexine 1 Diphenhydramine 0.5

TABLE 4 Examples with different oral care or nutraceutical embodiments.Numbers are given in percent by weight of each layer of the tablet Ex18Ex 19 Ex 20 Ex 21 Ex 22 Raw material (wt %) First layer Non-DC 48 48 4848 48 Erythritol DC Isomalt 47.75 47.75 47.75 47.75 47.75 Flavor 2 2 2 22 HIS 0.25 0.25 0.25 0.25 0.25 Magnesium 1 1 1 1 1 Stearate Binder HPC 11 1 1 1 Raw material (wt %) Second layer Gum base 20 20 20 20 20 sampleno. 101 Gum base 20 20 20 20 20 sample no. 102 DC Xylitol 27.295 27.02522.188 25.03 24.55 Non-DC Xylitol 27 27 27 27 27 Flavor 4 4 4 4 4Magnesium 1 1 1 1 1 Stearate HIS 0.25 0.25 0.25 0.25 0.25 Sodiumfluoride 0.022 0.022 0.022 0.02 0.023 Zinc acetate 0.433 0.433 0.430 — —Sodium — 0.270 0.270 — — bicarbonate Calcium — — 4.84 2.7 2.702pyrophosphate Vitamin D3 - — — — — 0.475 CaCO3premix

A specification of relevant compounds applied in the examples explainedabove are listed below.

HPC: Hydroxy propyl cellulose. Klucel Nutra D from AshlandNon DC Xylitol: Xivia C from DupontNon granulated Sorbitol: Pharm Sorbidex P 16656 from CargillNon DC Isomalt: Isomalt GS from Beneo PaltinitNon DC Mannitol: Pearlitol from RoquetteNon DC Maltitol: Maltisorb. P200 from RoquetteNon DC Erythritol: Zerose 16952 from CargillDC Erythritol—Zerose 16966 from CargillDC Xylitol—Xylitab 200 from DupontDC Isomalt—Isomalt DC 101 from Beneo PaltinitDC Mannitol—Pearlitol SD200 from RoquetteDC Maltitol—Sweetpearl 300 DC from Roquette

TABLE 5 Sensory evaluation of examples 8-12. Initial Total sensoryWatering effect experience Good/ Suitable mouthfeel 1-5 Acceptable(Acc)/during 10 minutes 1 low Ex Poor of chewing 5 high 8 Acc. Nice crunchyinitial chew. Fast 5 dissolving mint layer. Nice cooling mouthfeel andflavor burst. Ok softness texture. Ok lasting watering effect 9 GoodNice crunchy initial chew. Fast 4 dissolving mint layer. Nice coolingmouthfeel and flavor burst. Soft texture. Long lasting watering effect10 Acc Nice crunchy fast dissolving 5 mint layer. High flavor burst.Sandy particles over a long chewing period. Soft texture Long lastingwatering effect 11 Poor Nice crunchy fast dissolving 3 mint layer. Lowerflavor burst. Sandy particles over a long chewing period. A bit hardtexture over time Some lasting watering effect 12 Good Soft crunchyinitial chew. Fast 4 dissolving mint layer Fast flavor burst and highjuiciness. Long lasting watering effect

Evaluation

The tablets of Example 8-12 were evaluated with respect to mouthfeel.

The friability of Examples 8-12 was also measured according to EuropeanPharmacopoeia 9.1, test method 2.9.7. by using a pharmaceuticalfriability-tester PTF 10E from Pharma Test.

In particular Examples 8 and 12 were mentioned as having a veryattractive and nice initial crunch and the tablet polyols was dissolvingvery fast when masticated. It is noted in this context that theperceived salivation also promoted an initial fast transition of theparticles comprising gum base into a coherent residual.

It was also noted that the flavor perception was more fresh even inspite of the fact the applied flavor and amount of flavor was the samein both the inventive Examples and the “conventional” comparativeexamples (not shown) based on DC-erythritol in the first layer insteadof the non-DC erythritol applied in Examples 8-12.

In terms of active ingredients, Examples 13-17 did exhibit an attractivemouthfeel, an attractive taste and the tablet was unexpectedlyconsidered attractive in terms of e.g. buccal delivery of activeingredients, such as nicotine of example 13. Also active ingredientssuch as the caffeine Example 14 were considered surprisingly pleasantwhen considering that caffeine is known for its bitter taste.

Overall, the salivation was considered impressive.

1-54. (canceled)
 55. An oral delivery tablet suitable for activepharmaceutical ingredients comprising a population of particles, thepopulation of particles comprising a) directly compressible (DC) sugaralcohol particles, b) non-directly compressible (non-DC) sugar alcoholparticles and c) particles comprising gum base, wherein a first moduleof the tablet comprises a) and b) and a second module of the tabletcomprises c) and wherein the non-DC sugar alcohol particles provide thefirst module of the tablet with a plurality of discrete non-DC areas.56. The oral delivery tablet according to claim 55, wherein the non-DCsugar alcohol particles have not been granulated prior to tableting. 57.The oral delivery tablet according to claim 55, wherein the non-DC sugaralcohol particles are non-DC particles of erythritol, or non-DCparticles of maltitol, or non-DC particles of xylitol, or combinationsthereof.
 58. The oral delivery tablet according to claim 55, wherein thenon-DC sugar alcohol particles are non-DC erythritol particles.
 59. Theoral delivery tablet according to claim 55, wherein the tablet comprisessaid non-DC sugar alcohol particles in an amount of at least 10% byweight of the tablet.
 60. The oral delivery tablet according to claim55, wherein the tablet further comprises an oral care agent in theamount of at least 0.1% by weight of the tablet.
 61. The oral deliverytablet according to claim 55, wherein the tablet further comprises toothpaste in the amount of at least 0.1% by weight of the tablet. 62.(canceled)
 63. (canceled)
 64. (canceled)
 65. The oral delivery tabletaccording to claim 55, wherein the non-DC areas are evenly distributedin the first module of the tablet.
 66. The oral delivery tabletaccording to claim 55, wherein a series of at least 10 of said tabletseach comprises a gum base free module, and wherein the gum base freemodule comprises said non-DC sugar alcohol particles in an amountvarying with a relative standard deviation (RSD) below 10%. 67.(canceled)
 68. The oral delivery tablet according to claim 55, whereinthe tablet has a weight ratio between said non-DC sugar alcoholparticles and said DC sugar alcohol particles that is between 0.3 and1.2.
 69. The oral delivery tablet according to claim 55, wherein salivageneration upon mastication of the first module of the tablet is inducedcompared to a first module of the tablet where the discrete areas arebased on DC sugar alcohol particles.
 70. The oral delivery tabletaccording to claim 55, wherein the tablet generates more than 1.0 mLsaliva per 10 seconds within 30 seconds from onset of mastication. 71.The oral delivery tablet according to claim 55, wherein the tabletgenerates more than 0.5 mL saliva per 10 seconds within a period from 30to 90 seconds from onset of mastication.
 72. The oral delivery tabletaccording to claim 55, wherein the tablet further comprises an activepharmaceutical ingredient.
 73. (canceled)
 74. (canceled)
 75. The oralchewable tablet according to claim 55, wherein at least 30% by weight ofthe non-DC sugar alcohol particles have a particle size above 500 μm.76. The oral chewable tablet according to claim 55, wherein the non-DCsugar alcohol particles have an average size at least 50 μm larger thanthe average size of the DC sugar alcohol particles.
 77. The oraldelivery tablet according to claim 55, wherein the first module of thetablet comprises said non-DC sugar alcohol particles in an amount of atleast 10% by weight of the first module of the tablet.
 78. The oraldelivery tablet according to claim 55, wherein the first module of thetablet comprises said DC sugar alcohol particles in an amount of atleast 10% by weight of the first module of the tablet.
 79. An oraldelivery tablet suitable for active pharmaceutical ingredientscomprising a population of particles, the population of particlescomprising a) directly compressible (DC) sugar alcohol particles, b)non-directly compressible (non-DC) sugar alcohol particles and c)particles comprising gum base, wherein said population of particles istableted into a first module of the tablet and combined with a secondpopulation of particles that is tableted into a second module of thetablet and wherein the non-DC sugar alcohol particles provide the firstmodule of the tablet with a plurality of discrete non-DC areas.
 80. Anoral delivery tablet suitable for active pharmaceutical ingredientscomprising a population of particles, the population of particlescomprising a) directly compressible (DC) sugar alcohol particles, b)non-directly compressible (non-DC) sugar alcohol particles and c)particles comprising gum base, wherein a) and b) are tableted into afirst module of the tablet and c) is tableted into a second module ofthe tablet and wherein the first module of the tablet is free of gumbase.
 81. An oral delivery tablet suitable for active pharmaceuticalingredients comprising a first module having a plurality of directlycompressible (DC) sugar alcohol particles and a plurality ofnon-directly compressible (non-DC) sugar alcohol particles, said non-DCsugar particles forming a plurality of discrete non-DC areas, and asecond module having a plurality of particles comprising gum base. 82.The tablet according to claim 81, wherein the non-DC sugar alcoholparticles are not granulated.